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Vo TX, Peña D, Landau J, Nagpal AD. Venoarterial Extracorporeal Membrane Oxygenation in Adults With Septic Shock: Hope or Hype? Can J Cardiol 2025; 41:705-717. [PMID: 39892613 DOI: 10.1016/j.cjca.2025.01.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025] Open
Abstract
Septic shock is associated with significant morbidity and mortality, but a subset of patients with sepsis will experience transient myocardial depression, termed sepsis-associated cardiomyopathy, which markedly increases observed mortality. Although venoarterial extracorporeal membrane oxygenation (VA-ECMO) can provide temporary mechanical circulatory support in medically refractory sepsis, survival in patients with VA-ECMO for sepsis has been historically poor. Concerns regarding numerous potential harms associated with VA-ECMO, including further seeding of infection, exacerbation of inflammation and vasoplegia, bleeding, thrombosis, and distal limb ischemia have further tempered enthusiasm in the setting of sepsis. However, there may be a subset of patients with profound sepsis refractory to medical therapy that could potentially derive some benefit from VA-ECMO. This review provides an overview of the pathophysiology, diagnosis, and treatment of sepsis-associated cardiomyopathy and then focuses on the utility of VA-ECMO in this patient population. A summary of the scant published outcomes of VA-ECMO in sepsis-associated cardiomyopathy is provided, followed by a discussion of important management considerations to optimize outcomes in these extremely sick patients, and finally the pros and cons of VA-ECMO in the setting of sepsis are presented. Using available published data and current state-of-the-art practice, we conclude that VA-ECMO may be a reasonable consideration in highly selected patients with low ejection fraction sepsis-associated cardiomyopathy and refractory hypoperfusion in appropriately equipped health care systems, but more supportive data are required before VA-ECMO can be generally recommended in patients with septic shock.
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Affiliation(s)
- Thin Xuan Vo
- Division of Cardiac Surgery, Department of Surgery, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Diego Peña
- Division of Cardiac Surgery, Department of Surgery, Fundación Valle del Lili, ICESI University, Cali, Valle del Cauca, Colombia
| | - John Landau
- Division of Vascular Surgery, Department of Surgery, London Health Sciences Centre, Western University, London, Ontario, Canada; Critical Care Western, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - A Dave Nagpal
- Division of Cardiac Surgery, Department of Surgery, London Health Sciences Centre, Western University, London, Ontario, Canada; Critical Care Western, London Health Sciences Centre, Western University, London, Ontario, Canada.
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Li Y, Ren S, Zhou S. Advances in sepsis research: Insights into signaling pathways, organ failure, and emerging intervention strategies. Exp Mol Pathol 2025; 142:104963. [PMID: 40139086 DOI: 10.1016/j.yexmp.2025.104963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/13/2025] [Accepted: 03/19/2025] [Indexed: 03/29/2025]
Abstract
Sepsis is a complex syndrome resulting from an aberrant host response to infection. A hallmark of sepsis is the failure of the immune system to restore balance, characterized by hyperinflammation or immunosuppression. However, the net effect of immune system imbalance and the clinical manifestations are highly heterogeneous among patients. In recent years, research interest has shifted from focusing on the pathogenicity of microorganisms to the molecular mechanisms of host responses which is also associated with biomarkers that can help early diagnose sepsis and guide treatment decisions. Despite significant advancements in medical science, sepsis remains a major challenge in healthcare, contributing to substantial morbidity and mortality worldwide. Further research is needed to improve our understanding of this condition and develop novel therapies to improve outcomes for patients with sepsis. This review explores the related signal pathways of sepsis and underscores recent advancements in understanding its mechanisms. Exploration of diverse biomarkers and the emerging concept of sepsis endotypes offer promising avenues for precision therapy in the future.
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Affiliation(s)
- Yehua Li
- College of Life Sciences, Northwest Normal University, Lanzhou, Gansu 730070, PR China.
| | - Siying Ren
- College of Life Sciences, Northwest Normal University, Lanzhou, Gansu 730070, PR China
| | - Shen'ao Zhou
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, CAS. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, PR China.
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Liu Z, Li F, Li N, Chen Y, Chen Z. MicroRNAs as regulators of cardiac dysfunction in sepsis: pathogenesis and diagnostic potential. Front Cardiovasc Med 2025; 12:1517323. [PMID: 40041174 PMCID: PMC11876399 DOI: 10.3389/fcvm.2025.1517323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 01/29/2025] [Indexed: 03/06/2025] Open
Abstract
Introduction Sepsis, a life-threatening condition arising from an uncontrolled immune response to infection, can lead to organ dysfunction, with severe inflammation potentially causing multiple organ failures. Sepsis-induced cardiac dysfunction (SIMD) is a common and severe complication of sepsis, significantly increasing patient mortality. Understanding the pathogenesis of SIMD is crucial for improving treatment, and microRNAs (miRNAs) have emerged as important regulators in this process. Methods A comprehensive literature search was conducted in PubMed, Science Direct, and Embase databases up to September 2024. The search terms included ["miRNA" or "microRNA"] and ["Cardiac" or "Heart"] and ["Sepsis" or "Septic"], with the language limited to English. After initial filtering by the database search engine, Excel software was used to further screen references. Duplicate articles, those without abstracts or full texts, and review/meta-analyses or non-English articles were excluded. Finally, 106 relevant research articles were included for data extraction and analysis. Results The pathogenesis of SIMD is complex and involves mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis and pyroptosis, dysregulation of myocardial calcium homeostasis, myocardial inhibitory factors, autonomic nervous regulation disorders, hemodynamic changes, and myocardial structural alterations. miRNAs play diverse roles in SIMD. They are involved in regulating the above-mentioned pathological processes. Discussion Although significant progress has been made in understanding the role of miRNAs in SIMD, there are still challenges. Some studies on the pathogenesis of SIMD have limitations such as small sample sizes and failure to account for confounding factors. Research on miRNAs also faces issues like inconsistent measurement techniques and unclear miRNA-target gene relationships. Moreover, the translation of miRNA-based research into clinical applications is hindered by problems related to miRNA stability, delivery mechanisms, off-target effects, and long-term safety. In conclusion, miRNAs play a significant role in the pathogenesis of SIMD and have potential as diagnostic biomarkers. Further research is needed to overcome existing challenges and fully exploit the potential of miRNAs in the diagnosis and treatment of SIMD.
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Affiliation(s)
- Zhen Liu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Feiyang Li
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ningcen Li
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yong Chen
- Department of Critical Care Medicine, Tianjin Hospital of ITCWM Nankai Hospital, Tianjin, China
| | - Zelin Chen
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Zeng H, Xu J, Wu R, Wang X, Jiang Y, Wang Q, Guo J, Xiao F. FTO alleviated ferroptosis in septic cardiomyopathy via mediating the m6A modification of BACH1. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167307. [PMID: 38897256 DOI: 10.1016/j.bbadis.2024.167307] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/28/2024] [Accepted: 06/13/2024] [Indexed: 06/21/2024]
Abstract
Sepsis is a global health challenge that results in systemic inflammation, oxidative stress, and multi-organ dysfunction, with the heart being particularly susceptible. This study aimed to elucidate the effect of FTO, a key regulator in m6A methylation in septic cardiomyopathy, and its potential therapeutic implications. Cellular and animal models of septic myocardial injury were established. Moreover, it was revealed that ferroptosis, which is a form of programmed necrosis occurring with iron dependence, was activated within cardiomyocytes during septic conditions. The overexpression of FTO-suppressed ferroptosis alleviated heart inflammation and dysfunction and improved survival rates in vivo. However, the protective effects of FTO were attenuated by the overexpression of BACH1, which is a molecule negatively correlated with FTO. Mechanistically, FTO modulated the m6A modification of BACH1, suggesting a complex interplay in the regulation of cardiomyocyte damage and sepsis. Our findings reveal the potential of targeting the FTO/BACH1 axis and ferroptosis inhibitors as therapeutic strategies for sepsis-induced cardiac injuries.
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Affiliation(s)
- Hua Zeng
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Junmei Xu
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Rui Wu
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Xin Wang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yaqing Jiang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Qing Wang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jiali Guo
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Feng Xiao
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
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Ma W, Huang Z, Miao Y, Ma X, Zhang Z, Liu W, Xie P. ANXA1sp modulates the protective effect of Sirt3-induced mitophagy against sepsis-induced myocardial injury in mice. Acta Physiol (Oxf) 2024; 240:e14184. [PMID: 38822624 DOI: 10.1111/apha.14184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 06/03/2024]
Abstract
AIM Sepsis-induced myocardial injury (SIMI) may be associated with insufficient mitophagy in cardiomyocytes, but the exact mechanism involved remains unknown. Sirtuin 3 (Sirt3) is mainly found in the mitochondrial matrix and is involved in repairing mitochondrial function through means such as the activation of autophagy. Previously, we demonstrated that the annexin-A1 small peptide (ANXA1sp) can promote Sirt3 expression in mitochondria. In this study, we hypothesized that the activation of Sirt3 by ANXA1sp induces mitophagy, thereby providing a protective effect against SIMI in mice. METHODS A mouse model of SIMI was established via cecal ligation and puncture. Intraperitoneal injections of ANXA1sp, 3TYP, and 3MA were administered prior to modeling. After successful modeling, IL-6, TNF-α, CK-MB, and CTn-I levels were measured; cardiac function was assessed using echocardiography; myocardial mitochondrial membrane potential, ROS, and ATP production were determined; myocardial mitochondrial ultrastructure was observed using transmission electron microscopy; and the expression levels of Sirt3 and autophagy-related proteins were detected using western blotting. RESULTS ANXA1sp significantly reduced serum IL-6, TNF-α, CK-MB, and CTn-I levels; decreased myocardial ROS production; increased mitochondrial membrane potential and ATP synthesis; and improved myocardial mitochondrial ultrastructure in septic mice. Furthermore, ANXA1sp promoted Sirt3 expression and activated the AMPK-mTOR pathway to induce myocardial mitophagy. These protective effects of ANXA1sp were reversed upon treatment with the Sirt3 blocker, 3-TYP. CONCLUSION ANXA1sp can reverse SIMI, and the underlying mechanism may be related to the activation of the AMPK-mTOR pathway following upregulation of Sirt3 by ANXA1sp, which, in turn, induces autophagy.
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Affiliation(s)
- Wanyu Ma
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi), Zunyi Medical University, Zunyi, China
| | - Zhijia Huang
- Department of Critical Care Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Yanmei Miao
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi), Zunyi Medical University, Zunyi, China
| | - Xinglong Ma
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi), Zunyi Medical University, Zunyi, China
| | - Zhiquan Zhang
- Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Wenjie Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Peng Xie
- Department of Critical Care Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
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Chen M, Huang S, Weng S, Weng J, Guo R, Shi B, Liu D. Songorine ameliorates LPS-induced sepsis cardiomyopathy by Wnt/β-catenin signaling pathway-mediated mitochondrial biosynthesis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4713-4725. [PMID: 38133657 DOI: 10.1007/s00210-023-02897-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
Septic cardiomyopathy (SCM) is manifested by impairment of cardiac contractile function with myocardial mitochondrial dysregulation. Natural product, songorine (SGR), a diterpenoid alkaloid derived from the lateral root of Aconitum carmichaeli, has been reported for the treatment of heart failure. Here, the protective role of SGR in heart injury of SCM was investigated and its underlying action of mechanism was explored. Firstly, the mouse and cardiomyocytes (H9C2 cell) SCM model induced by LPS were established to evaluate the therapeutic effect of SGR. The in vivo results exhibited that SGR rescued the survival rate of SCM mice, restored the loss of ejection fraction (EF) and fractional shortening (FS), and reduced left ventricular systolic diameter and left ventricular diastole diameter (LVIDs, LVIDd) by echocardiography. SGR improved the mitochondrial biosynthesis and myocardial fiber structure and arranged them neatly by transmission electron microscope (TEM). Further, SGR inhibited inflammatory targets myeloperoxidase (MPO) and tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and plasminogen activator inhibitor-1 (PAI-1). And SGR activated the mitochondrial biosynthesis-related peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), β-catenin, and matrix metallopeptidase 2 (MMP2) proteins. Meanwhile, the in vitro results showed that SGR promoted the increased the myocardial H9C2 cell viability, and mitochondrial biosynthesis and structure. SGR also blocked the inflammatory factors and reversed PGC-1α, β-catenin, and MMP2 in vitro, while SGR alleviated the myocardial cell apoptosis via flow cytometry. The findings indicate that SGR mitigates sepsis-caused myocardial damage by Wnt/β-catenin signaling pathway-mediated mitochondrial biosynthesis. SGR may be a promising candidate for treatment of SCM.
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Affiliation(s)
- Min Chen
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, No. 999 Dongzhen East Road, Licheng District, Putian, 351100, Fujian, China
| | - Shanjiao Huang
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, No. 999 Dongzhen East Road, Licheng District, Putian, 351100, Fujian, China
| | - Shuoyun Weng
- School of Ophthalmology&Optometry, Wenzhou Medical University, Wenzhou, 325000, China
| | - Junting Weng
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, No. 999 Dongzhen East Road, Licheng District, Putian, 351100, Fujian, China
| | - Rongjie Guo
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, No. 999 Dongzhen East Road, Licheng District, Putian, 351100, Fujian, China
| | - Bingbing Shi
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, No. 999 Dongzhen East Road, Licheng District, Putian, 351100, Fujian, China
| | - Danjuan Liu
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, No. 999 Dongzhen East Road, Licheng District, Putian, 351100, Fujian, China.
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Duan F, Li L, Liu S, Tao J, Gu Y, Li H, Yi X, Gong J, You D, Feng Z, Yu T, Tan H. Cortistatin protects against septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-NLRP3 pathway. Int Immunopharmacol 2024; 134:112186. [PMID: 38733824 DOI: 10.1016/j.intimp.2024.112186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND Although the pathophysiological mechanism of septic cardiomyopathy has been continuously discovered, it is still a lack of effective treatment method. Cortistatin (CST), a neuroendocrine polypeptide of the somatostatin family, has emerged as a novel cardiovascular-protective peptide, but the specific mechanism has not been elucidated. PURPOSE The aim of our study is to explore the role of CST in cardiomyocytes pyroptosis and myocardial injury in sepsis and whether CST inhibits cardiomyocytes pyroptosis through specific binding with somastatin receptor 2 (SSTR2) and activating AMPK/Drp1 signaling pathway. METHODS AND RESULTS In this study, plasma CST levels were significantly high and were negatively correlated with N-terminal pro-B type natriuretic peptide (NT-proBNP), a biomarker for cardiac dysfunction, in patients with sepsis. Exogenous administration of CST significantly improved survival rate and cardiac function in mouse models of sepsis by inhibiting the activation of the NLRP3 inflammasome and pyroptosis of cardiomyocytes (decreased cleavage of caspase-1, IL-1β and gasdermin D). Pharmacological inhibition and genetic ablation revealed that CST exerted anti-pyroptosis effects by specifically binding to somatostatin receptor subtype 2 (SSTR2), thus activating AMPK and inactivating Drp1 to inhibit mitochondrial fission in cardiomyocytes. CONCLUSIONS This study is the first to report that CST attenuates septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-Drp1-NLRP3 pathway. Importantly, CST specifically binds to SSTR2, which promotes AMPK phosphorylation, inhibits Drp1-mediated mitochondrial fission, and reduces ROS levels, thereby inhibiting NLRP3 inflammasome activation-mediated pyroptosis and alleviating sepsis-induced myocardial injury.
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Affiliation(s)
- Fengqi Duan
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Li Li
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510012, Guangdong, China
| | - Sijun Liu
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Jun Tao
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Yang Gu
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510012, Guangdong, China
| | - Huangjing Li
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Xiaoling Yi
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510012, Guangdong, China
| | - Jianfeng Gong
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Daiting You
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Zejiang Feng
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Tao Yu
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510012, Guangdong, China
| | - Hongmei Tan
- Department of Pathophysiology, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Laboratory Animal Center, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
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Casper E, El Wakeel L, Sabri N, Khorshid R, Fahmy SF. Melatonin: A potential protective multifaceted force for sepsis-induced cardiomyopathy. Life Sci 2024; 346:122611. [PMID: 38580195 DOI: 10.1016/j.lfs.2024.122611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 03/19/2024] [Accepted: 04/02/2024] [Indexed: 04/07/2024]
Abstract
Sepsis is a life-threatening condition manifested by organ dysfunction caused by a dysregulated host response to infection. Lung, brain, liver, kidney, and heart are among the affected organs. Sepsis-induced cardiomyopathy is a common cause of death among septic patients. Sepsis-induced cardiomyopathy is characterized by an acute and reversible significant decline in biventricular both systolic and diastolic function. This is accompanied by left ventricular dilatation. The pathogenesis underlying sepsis-induced cardiomyopathy is multifactorial. Hence, targeting an individual pathway may not be effective in halting the extensive dysregulated immune response. Despite major advances in sepsis management strategies, no effective pharmacological strategies have been shown to treat or even reverse sepsis-induced cardiomyopathy. Melatonin, namely, N-acetyl-5-methoxytryptamine, is synthesized in the pineal gland of mammals and can also be produced in many cells and tissues. Melatonin has cardioprotective, neuroprotective, and anti-tumor activity. Several literature reviews have explored the role of melatonin in preventing sepsis-induced organ failure. Melatonin was found to act on different pathways that are involved in the pathogenesis of sepsis-induced cardiomyopathy. Through its antimicrobial, anti-inflammatory, and antioxidant activity, it offers a potential role in sepsis-induced cardiomyopathy. Its antioxidant activity is through free radical scavenging against reactive oxygen and nitrogen species and modulating the expression and activity of antioxidant enzymes. Melatonin anti-inflammatory activities control the overactive immune system and mitigate cytokine storm. Also, it mitigates mitochondrial dysfunction, a major mechanism involved in sepsis-induced cardiomyopathy, and thus controls apoptosis. Therefore, this review discusses melatonin as a promising drug for the management of sepsis-induced cardiomyopathy.
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Affiliation(s)
- Eman Casper
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| | - Lamia El Wakeel
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| | - Nagwa Sabri
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| | - Ramy Khorshid
- Department of Cardiovascular and Thoracic Surgery, Ain Shams University Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Sarah F Fahmy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Bai X, Yang L, Liu R, Tang Y, Yang L, Ma L, Chen M, Zhang L. Long Noncoding RNA SOX2OT Ameliorates Sepsis-Induced Myocardial Injury by Inhibiting Cellular Pyroptosis Through Mediating the EZH2/Nrf-2/NLRP3 Signaling Pathway. J Inflamm Res 2024; 17:3115-3127. [PMID: 38774445 PMCID: PMC11107952 DOI: 10.2147/jir.s451643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 04/16/2024] [Indexed: 05/24/2024] Open
Abstract
Objective Cellular pyroptosis is a pro-inflammatory mode of programmed cell death that has been identified in recent years, and studies have shown that the LncRNA SOX2OT regulates myocardial injury during sepsis, but the exact regulatory mechanism is unclear. The aim of this study was to assess the role of SOX2OT in regulating cardiomyocyte injury during sepsis cardiomyopathy. Methods Rat cardiomyocytes, C57BL/6 mice, and transgenic mice were divided into four groups: control, LPS, LPS+ knockout LncRNA SOX2OT, and LPS+ overexpression LncRNA SOX2OT. Inflammatory factor levels were detected by qPCR. Associated proteins and gene expression were detected by Western blotting and qPCR. Dual luciferase was used to detect the target genes of SOX2OT. Nrf2 and EZH2 knockdown and overexpression cell lines were established, and the expression of related genes was detected by qPCR. Results Results In this study, we found that SOX2OT knockdown exacerbated LPS-induced levels of inflammatory factors and procalcitoninogen (PCT), and increased the expression of pyroptosis-related proteins and LDH. The results of dual luciferase reporter gene assay showed that EZH2 is the target gene of SOX2OT, and overexpression of SOX2OT decreased the expression of EZH2; we also found that knockdown of EZH2 in H9c2 cells decreased the expression of Nrf2, which was positively correlated with the expression level of NLRP3. Further in vivo results showed that overexpression of SOX2OT attenuated SIMD (sepsis-induced myocardial dysfunction), as evidenced by improved myocardial structural integrity and reduced inflammatory cell infiltration. The expression of pyroptosis-related proteins and LDH was significantly increased in the mice in the LPS group; this effect was reversed by overexpression of SOX2OT, and potentiated by knockdown of SOX2OT. Conclusion Our data reveal a novel mechanism by which SOX2OT inhibits cardiomyocyte sepsis through the EZH2/Nrf-2/NLRP3 pathway, thereby attenuating septic myocardial injury, which may contribute to the development of new therapeutic strategies.
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Affiliation(s)
- Xue Bai
- Department of Emergency, The Third Clinical Medical College of Ningxia Medical University, Yinchuan, People’s Republic of China
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - LiTing Yang
- Department of Emergency, The Third Clinical Medical College of Ningxia Medical University, Yinchuan, People’s Republic of China
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - Ruxin Liu
- Department of Emergency, The Third Clinical Medical College of Ningxia Medical University, Yinchuan, People’s Republic of China
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - YuJiao Tang
- Department of Emergency, The Third Clinical Medical College of Ningxia Medical University, Yinchuan, People’s Republic of China
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - Long Yang
- Department of Emergency, The Third Clinical Medical College of Ningxia Medical University, Yinchuan, People’s Republic of China
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - Lingna Ma
- Department of Emergency, The Third Clinical Medical College of Ningxia Medical University, Yinchuan, People’s Republic of China
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - MengFei Chen
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
| | - Ling Zhang
- Department of Emergency, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China
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Basak B, Akashi-Takamura S. IRF3 function and immunological gaps in sepsis. Front Immunol 2024; 15:1336813. [PMID: 38375470 PMCID: PMC10874998 DOI: 10.3389/fimmu.2024.1336813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 01/22/2024] [Indexed: 02/21/2024] Open
Abstract
Lipopolysaccharide (LPS) induces potent cell activation via Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), often leading to septic death and cytokine storm. TLR4 signaling is diverted to the classical acute innate immune, inflammation-driving pathway in conjunction with the classical NF-κB pivot of MyD88, leading to epigenetic linkage shifts in nuclear pro-inflammatory transcription and chromatin structure-function; in addition, TLR4 signaling to the TIR domain-containing adapter-induced IFN-β (TRIF) apparatus and to nuclear pivots that signal the association of interferons alpha and beta (IFN-α and IFN-β) with acute inflammation, often coupled with oxidants favor inhibition or resistance to tissue injury. Although the immune response to LPS, which causes sepsis, has been clarified in this manner, there are still many current gaps in sepsis immunology to reduce mortality. Recently, selective agonists and inhibitors of LPS signals have been reported, and there are scattered reports on LPS tolerance and control of sepsis development. In particular, IRF3 signaling has been reported to be involved not only in sepsis but also in increased pathogen clearance associated with changes in the gut microbiota. Here, we summarize the LPS recognition system, main findings related to the IRF3, and finally immunological gaps in sepsis.
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Affiliation(s)
- Bristy Basak
- Department of Microbiology and Immunology, School of Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Sachiko Akashi-Takamura
- Department of Microbiology and Immunology, School of Medicine, Aichi Medical University, Nagakute, Aichi, Japan
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11
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Salami OM, Habimana O, Peng JF, Yi GH. Therapeutic Strategies Targeting Mitochondrial Dysfunction in Sepsis-induced Cardiomyopathy. Cardiovasc Drugs Ther 2024; 38:163-180. [PMID: 35704247 DOI: 10.1007/s10557-022-07354-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/06/2022] [Indexed: 11/03/2022]
Abstract
Sepsis is an increasingly worldwide problem; it is currently regarded as a complex life-threatening dysfunction of one or more organs as a result of dysregulated host immune response to infections. The heart is one of the most affected organs, as roughly 10% to 70% of sepsis cases are estimated to turn into sepsis-induced cardiomyopathy (SIC). SIC can be defined as a reversible myocardial dysfunction characterized by dilated ventricles, impaired contractility, and decreased ejection fraction. Mitochondria play a critical role in the normal functioning of cardiac tissues as the heart is highly dependent on its production of adenosine triphosphate (ATP), its damage during SIC includes morphology impairment, mitophagy, biogenesis disequilibrium, electron transport chain disturbance, molecular damage from the actions of pro-inflammatory cytokines and many other different impairments that are major contributing factors to the severity of SIC. Although mitochondria-targeted therapies usage is still inadequate in clinical settings, the preclinical study outcomes promise that the implementation of these therapies may effectively treat SIC. This review summarizes the different therapeutic strategies targeting mitochondria structure, quality, and quantity abnormalities for the treatment of SIC.
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Affiliation(s)
| | - Olive Habimana
- International College, University of South China, 28, W Changsheng Road, Hengyang, 421001, Hunan, China
| | - Jin-Fu Peng
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang Medical School, University of South China, 28, W Changsheng Road, Hengyang, 421001, Hunan, China
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, 28, W Changsheng Road, Hengyang, 421001, Hunan, China
| | - Guang-Hui Yi
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang Medical School, University of South China, 28, W Changsheng Road, Hengyang, 421001, Hunan, China.
- Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, 28, W Changsheng Road, Hengyang, 421001, Hunan, China.
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12
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Xu Y, Zhang X, Tang X, Zhang C, Cahoon JG, Wang Y, Li H, Lv X, Wang Y, Wang Z, Wang H, Yang D. Dexmedetomidine post-treatment exacerbates metabolic disturbances in septic cardiomyopathy via α 2A-adrenoceptor. Biomed Pharmacother 2024; 170:115993. [PMID: 38091635 DOI: 10.1016/j.biopha.2023.115993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 01/10/2024] Open
Abstract
Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α2A-adrenoceptor deficient (Adra2a-/-) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a-/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a-/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α2A-adrenoceptor dependent manner.
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Affiliation(s)
- Yaqian Xu
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Xue Zhang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Xiangxu Tang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Chanjuan Zhang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Jason G Cahoon
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
| | - Yingwei Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Hongmei Li
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Xiuxiu Lv
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Yiyang Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Zhi Wang
- Key Laboratory of Occupational Environment and Health, Guangzhou Twelfth People's Hospital, Guangzhou 510620, China
| | - Huadong Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
| | - Duomeng Yang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
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13
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Lukić I, Mihić D, Varžić SC, Relatić KS, Zibar L, Loinjak D, Ćurić ŽB, Klobučar L, Maričić L. Septic Cardiomyopathy. Rev Cardiovasc Med 2024; 25:23. [PMID: 39077653 PMCID: PMC11262393 DOI: 10.31083/j.rcm2501023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/20/2023] [Accepted: 12/01/2023] [Indexed: 07/31/2024] Open
Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Studies on septic cardiomyopathy report a wide range of prevalence ranging from 10% to 70%. Myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Mitochondrial dysfunction is the leading problem in the development of septic cardiomyopathy and includes oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism, and mitophagy. Echocardiography provides several possibilities for the diagnosis of septic cardiomyopathy. Systolic and diastolic dysfunction of left ventricular is present in 50-60% of patients with sepsis. Right ventricular dysfunction is present in 50-55% of cases, while isolated right ventricular dysfunction is present in 47% of cases. Left ventricle (LV) diastolic dysfunction is very common in septic shock, and it represents an early biomarker, it has prognostic significance. Right ventricular dysfunction associated with sepsis patients with worse early prognosis. Global longitudinal stress and magnetic resonance imaging (MRI) of the heart are sufficiently sensitive methods, but at the same time MRI of the heart is difficult to access in intensive care units, especially when dealing with critically ill patients. Previous research has identified two biomarkers as a result of the integrated mitochondrial response to stress, and these are fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15). Both of the mentioned biomarkers can be easily quantified in serum or plasma, but they are difficult to be specific in patients with multiple comorbidities. Mitochondrial dysfunction is also associated with reduced levels of miRNA (microRNA), some research showed significance of miRNA in sepsis-induced myocardial dysfunction, but further research is needed to determine the clinical significance of these molecules in septic cardiomyopathy. Therapeutic options in the treatment of septic cardiomyopathy are not specific, and include the optimization of hemodynamic parameters and the use of antibiotic thera-pies with targeted action. Future research aims to find mechanisms of targeted action on the initial mechanisms of the development of septic cardiomyopathy.
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Affiliation(s)
- Ivana Lukić
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Heart and Vascular Diseases, University Hospital Centre Osijek, 31000 Osijek, Croatia
| | - Damir Mihić
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Pulmology and Intensive Care Medicine, University Hospital Centre Osijek, 31000 Osijek, Croatia
| | - Silvija Canecki Varžić
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Endocrinology, University Hospital Centre Hospital Osijek, 31000 Osijek, Croatia
| | - Kristina Selthofer Relatić
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Heart and Vascular Diseases, University Hospital Centre Osijek, 31000 Osijek, Croatia
| | - Lada Zibar
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Nephrology, University Hospital Merkur, Zagreb, 10000 Zagreb, Croatia
| | - Domagoj Loinjak
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Pulmology and Intensive Care Medicine, University Hospital Centre Osijek, 31000 Osijek, Croatia
| | - Željka Breškić Ćurić
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Internal Medicine, General Hospital Vinkovci, 32100 Vinkovci, Croatia
| | - Lucija Klobučar
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Heart and Vascular Diseases, University Hospital Centre Osijek, 31000 Osijek, Croatia
| | - Lana Maričić
- Faculty of Medicine, University J. J. Strossmayer in Osijek, 31000 Osijek, Croatia
- Department of Heart and Vascular Diseases, University Hospital Centre Osijek, 31000 Osijek, Croatia
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14
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Liu H, Hu Q, Ren K, Wu P, Wang Y, Lv C. ALDH2 mitigates LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING pathway. Mol Med 2023; 29:171. [PMID: 38124089 PMCID: PMC10731778 DOI: 10.1186/s10020-023-00769-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/10/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Sepsis is a severe syndrome of organ dysfunction that often leads to cardiac dysfunction and endangers life. The role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in LPS-induced myocardial injury is unclear. The purpose of this study was to assess the role of ALDH2 in lipopolysaccharide (LPS)-induced myocardial injury and the regulatory mechanism and to identify potential therapeutic strategies for treating this condition. METHODS An in vivo model was established by 12 h of LPS (10 mg/kg, intraperitoneal injection) stimulation, and an in vitro model was generated by stimulating H9C2 cells with LPS (10 μg/ml) for 12 h. We then used the ALDH2 activator Alda-1 and the ALDH2 inhibitor daidzin to assess their effects on LPS-induced cardiac injury. Cardiac function in mice was evaluated by using cardiac ultrasound. We used various methods to evaluate inflammation, apoptosis, and oxidative stress, including ELISA, flow cytometry, JC-1 staining, Western blotting, and DCFH-DA staining. Additionally, we used a small interfering RNA (siRNA) to knock down cyclic GMP-AMP synthase (cGAS) to further investigate the relationship between ALDH2 and cGAS in LPS-induced cardiac injury. RESULTS LPS-induced cardiac dysfunction and increased the levels of the cardiac injury markers creatine kinase-MB (CKMB) and lactate dehydrogenase (LDH) in vivo. This change was accompanied by an increase in reactive oxygen species (ROS) levels, which exacerbated the oxidative stress response and regulated apoptosis through cleaved caspase-3, BAX, BCL-2. The expression of inflammatory cytokines such as IL-6/IL-1β/TNF-α was also upregulated. However, these effects were reversed by pretreatment with Alda-1 via the inhibition of cGAS/stimulator of interferon genes (STING) signaling pathway. Interestingly, LPS, Alda-1 and daidzin altered the activity of ALDH2 but did not regulate its protein expression. Knocking down cGAS in H9C2 cardiomyocytes alleviated LPS-induced cardiac inflammation, apoptosis, and ROS production and weakened the synergistic effect of daidzin. CONCLUSION We demonstrated that ALDH2 alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING signaling pathway, thereby protecting against LPS-induced cardiac injury. This study identifies a novel therapeutic approach for treating sepsis-induced cardiomyopathy (SIC).
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Affiliation(s)
- Haoran Liu
- Emergency and Trauma College, Hainan Medical University, Haikou, China
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, China
| | - Qin Hu
- Emergency and Trauma College, Hainan Medical University, Haikou, China
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, China
| | - Ke Ren
- Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Pengxin Wu
- Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yang Wang
- Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
| | - Chuanzhu Lv
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, China.
- Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences (No. 2019RU013), Hainan Medical University, Haikou, China.
- Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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15
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Gao Z, Zheng C, Xing Y, Zhang X, Bai Y, Chen C, Zheng Y, Wang W, Zhang H, Meng Y. Polo-like kinase 1 promotes sepsis-induced myocardial dysfunction. Int Immunopharmacol 2023; 125:111074. [PMID: 37879229 DOI: 10.1016/j.intimp.2023.111074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/26/2023] [Accepted: 10/10/2023] [Indexed: 10/27/2023]
Abstract
Sepsis-induced myocardial dysfunction (SIMD) is the main cause of mortality in sepsis. In this study, we identified Polo-like kinase 1 (Plk-1) is a promoter of SIMD. Plk-1 expression was increased in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice. Plk-1 was identified as a kinase of inhibitor of kappa B kinase alpha (IKKα). Plk-1 inhibition impeded NF-κB signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD.
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Affiliation(s)
- Zhenqiang Gao
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China
| | - Cuiting Zheng
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China; State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yaqi Xing
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China
| | - Xiyu Zhang
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China
| | - Yunfei Bai
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China
| | - Chen Chen
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Zheng
- Department of Pharmacology, Capital Medical University, Beijing, China
| | - Wen Wang
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China; National Demonstration Center for Experimental Basic Medical Education, Capital Medical University, Beijing, China
| | - Hongbing Zhang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Meng
- Department of Pathology, Beijing Lab for Cardiovascular Precision Medicine, Key Laboratory of Medical Engineering for Cardiovascular Disease, Capital Medical University, Beijing, China.
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16
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Zhang L, Qi D, Peng M, Meng B, Wang X, Zhang X, Zuo Z, Li L, Wang Z, Zou W, Hu Z, Qian Z. Decoding molecular signature on heart of septic mice with distinct left ventricular ejection fraction. iScience 2023; 26:107825. [PMID: 37736036 PMCID: PMC10509301 DOI: 10.1016/j.isci.2023.107825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/07/2023] [Accepted: 08/31/2023] [Indexed: 09/23/2023] Open
Abstract
Dysregulated cardiac function after sepsis in intensive care unit is known to predict poor long-term outcome and increase mortality. Their pathological feature and molecular mechanism remain unclear. We observed that septic patients with depressed left ventricular ejection fraction (LVEF) have the highest in-hospital and 28 days mortality comparing to patients with hyperdynamic LVEF or with heart failure with preserved LVEF. Echocardiograms reveal that survivors post cecum ligation and puncture (CLP) on rodents have stable LVEF and non-survivors have fluctuated LVEF at CLP early phase. CLP-induced mice fall into three groups based on LVEF 24 h post-surgery: high-, low-, and normal-LVEF. Transcriptomic and proteomic analyses identify jointly and distinctively changed genes, proteins and biologically essential pathways in left ventricles from three CLP groups. Notably, transmission electron microscopy shows different mitochondrial and sarcomere defects associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury.
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Affiliation(s)
- Lina Zhang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha, Changsha 410008, China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha 410008, China
| | - Desheng Qi
- Department of Emergency Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Milin Peng
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha, Changsha 410008, China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha 410008, China
| | - Binbin Meng
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xinrun Wang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaolei Zhang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhihong Zuo
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Li Li
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha, Changsha 410008, China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha 410008, China
| | - Zhanwen Wang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha, Changsha 410008, China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha 410008, China
| | - Wenxuan Zou
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Zhonghua Hu
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha, Changsha 410008, China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha 410008, China
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhaoxin Qian
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) Changsha, Changsha 410008, China
- Hunan Provincial Clinical Research Center for Critical Care Medicine, Changsha 410008, China
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17
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Zhu H, Wang J, Xin T, Chen S, Hu R, Li Y, Zhang M, Zhou H. DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction. Cell Mol Life Sci 2023; 80:213. [PMID: 37464072 PMCID: PMC11072740 DOI: 10.1007/s00018-023-04863-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/01/2023] [Accepted: 07/07/2023] [Indexed: 07/20/2023]
Abstract
Dual specificity phosphatase 1 (DUSP1) and valosin-containing protein (VCP) have both been reported to regulate mitochondrial homeostasis. However, their impact on mitochondrial quality control (MQC) and myocardial function during LPS-induced endotoxemia remains unclear. We addressed this issue by modeling LPS-induced endotoxemia in DUSP1 transgenic (DUSP1TG) mice and in cultured DUSP1-overexpressing HL-1 cardiomyocytes. Accompanying characteristic structural and functional deficits, cardiac DUSP1 expression was significantly downregulated following endotoxemia induction in wild type mice. In contrast, markedly reduced myocardial inflammation, cardiomyocyte apoptosis, cardiac structural disorder, cardiac injury marker levels, and normalized systolic/diastolic function were observed in DUSP1TG mice. Furthermore, DUSP1 overexpression in HL-1 cells significantly attenuated LPS-mediated mitochondrial dysfunction by preserving MQC, as indicated by normalized mitochondrial dynamics, improved mitophagy, enhanced biogenesis, and attenuated mitochondrial unfolded protein response. Molecular assays showed that VCP was a substrate of DUSP1 and the interaction between DUSP1 and VCP primarily occurred on the mitochondria. Mechanistically, DUSP1 phosphatase domain promoted the physiological DUSP1/VCP interaction which prevented LPS-mediated VCP Ser784 phosphorylation. Accordingly, transfection with a phosphomimetic VCP mutant abolished the protective actions of DUSP1 on MQC and aggravated inflammation, apoptosis, and contractility/relaxation capacity in HL-1 cardiomyocytes. These findings support the involvement of the novel DUSP1/VCP/MQC pathway in the pathogenesis of endotoxemia-caused myocardial dysfunction.
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Affiliation(s)
- Hang Zhu
- Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, 100048, China
| | - Jin Wang
- Department of Vascular Medicine, Peking University Shougang Hospital, Beijing, 100144, China
| | - Ting Xin
- Department of Cardiology, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
| | - Shanshan Chen
- Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, 100048, China
| | - Ruiying Hu
- Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, 100048, China
| | - Yukun Li
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Mingming Zhang
- Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
| | - Hao Zhou
- Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, 100048, China.
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18
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Ullah K, Li Y, Lin Q, Pan K, Nguyen T, Aniruddhsingh S, Su Q, Sharp W, Wu R. Comparative Analysis of Whole Transcriptome Profiles in Septic Cardiomyopathy: Insights from CLP- and LPS-Induced Mouse Models. Genes (Basel) 2023; 14:1366. [PMID: 37510271 PMCID: PMC10379808 DOI: 10.3390/genes14071366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, with septic cardiomyopathy being a common and severe complication. Despite its significant clinical impact, the molecular mechanisms underlying sepsis-induced cardiomyopathy (SICM) remain incompletely understood. In this study, we performed a comparative analysis of whole transcriptome profiles using RNA sequencing in mouse hearts in two widely used mouse models of septic cardiomyopathy. CLP-induced sepsis was achieved by surgical cecal ligation and puncture, while LPS-induced sepsis was induced using a 5 mg/kg intraperitoneal (IP) injection of lipopolysaccharide (LPS). For consistency, we utilized sham-operated mice as the control for septic models. Our aim was to identify key genes and pathways involved in the development of septic cardiomyopathy and to evaluate the similarities and differences between the two models. Our findings demonstrated that both the CLP and lipopolysaccharide LPS methods could induce septic heart dysfunction within 24 h. We identified common transcriptional regulatory regions in the septic hearts of both models, such as Nfkb1, Sp1, and Jun. Moreover, differentially expressed genes (DEGs) in comparison to control were involved in shared pathways, including regulation of inflammatory response, regulation of reactive oxygen species metabolic process, and the JAK-STAT signaling pathway. However, each model presented distinctive whole transcriptome expression profiles and potentially diverse pathways contributing to sepsis-induced heart failure. This extensive comparison enhances our understanding of the molecular basis of septic cardiomyopathy, providing invaluable insights. Accordingly, our study also contributes to the pursuit of effective and personalized treatment strategies for SICM, highlighting the importance of considering the specific causative factors.
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Affiliation(s)
- Karim Ullah
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA (T.N.)
| | - Yan Li
- Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA; (Y.L.); (Q.L.)
| | - Qiaoshan Lin
- Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA; (Y.L.); (Q.L.)
| | - Kaichao Pan
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA (T.N.)
| | - Tu Nguyen
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA (T.N.)
| | | | - Qiaozhu Su
- Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast BT9 5DL, UK;
| | - Willard Sharp
- Emergency Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Rongxue Wu
- Section of Cardiology, Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA (T.N.)
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Cai Z, He J, Jiang J, Zhao Z, Shu Y. Systematic investigation of the material basis, multiple mechanisms and quality control of Simiao Yong'an decoction combined with antibiotic in the treatment of sepsis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154910. [PMID: 37267690 DOI: 10.1016/j.phymed.2023.154910] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/12/2023] [Accepted: 05/28/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND Sepsis is one of the major threats to human health with high mortality. Simiao Yong'an decoction (SMYAD) has the efficacy of anti-inflammation, improving coagulation and microcirculation, which is applicable for the clinical assistance treatment of sepsis. Yet, its material basis and relevant mechanisms are still vague. PURPOSE Explore the quality markers (Q-markers), biomarkers and potential mechanisms of SMYAD combined with imipenem/cilastatin sodium for anti-sepsis. METHODS Linear-Trap-LC/MSn was employed to profile the compounds in the extract and medicated serum of SMYAD. Then, the components and targets obtained from databases were applied to network pharmacology. Q-markers' range was narrowed via the affinity of three times docking and determined as per its screening criteria. Also, the content of them was detected by HPLC. Next, cecal ligation and puncture (CLP) model was reproduced to observe the effect of SMYAD united antibiotic by survival rate, histopathology score, ELISA, western blot and qPCR. Finally, metabolomics based upon GC-MS was exerted to discover the differential endogenous metabolites, metabolic pathway and joint pathway of SMYAD combined with antibiotic for sepsis. RESULTS The 25 serum migrant ingredients derived from 113 chemical compounds of SMYAD were identified for the first time, and 6 components were determined as the Q-markers of SMYAD. The enrichment analysis indicated that the potential mechanism was mainly associated with the IL-17 signaling pathway, complement-coagulation cascades signaling pathway and VEGF signaling pathway. Then, SMYAD united antibiotic declined the mortality of septic rats, restored cytokine levels, ameliorated histopathological lesions and decreased the mRNA and protein expression of target proteins in a dose-dependent way. Furthermore, 8 differential metabolites were regarded as latent biomarkers related to the antiseptic effect of SMYAD united antibiotic, which were mainly involved in the Citrate cycle (TCA cycle) metabolic pathway. CONCLUSIONS Different skeletons of compounds, including iridoids, phenylpropanoids, organic acids, triterpenes and others, were the main compositions of SMYAD. Among them, 6 components were determined as the Q-markers, which provided a basis for the construction of quality standards for this ancient classic formula. The combination therapy of SMYAD and antibiotic obviously ameliorated inflammatory reaction, coagulation dysfunction and microcirculation abnormalities for sepsis by inhibiting IL-17 signaling pathway, complement-coagulation cascades signaling pathway and VEGF signaling pathway.
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Affiliation(s)
- Zhihui Cai
- School of Pharmacy, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Jinjin He
- School of Pharmacy, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Jun Jiang
- School of Pharmacy, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.
| | - Zihan Zhao
- School of Pharmacy, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
| | - Ye Shu
- School of Pharmacy, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China
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Qin S, Ren Y, Feng B, Wang X, Liu J, Zheng J, Li K, Chen M, Chen T, Mei H, Fu X. ANXA1sp Protects against Sepsis-Induced Myocardial Injury by Inhibiting Ferroptosis-Induced Cardiomyocyte Death via SIRT3-Mediated p53 Deacetylation. Mediators Inflamm 2023; 2023:6638929. [PMID: 37057132 PMCID: PMC10089776 DOI: 10.1155/2023/6638929] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 03/14/2023] [Accepted: 03/28/2023] [Indexed: 04/08/2023] Open
Abstract
Sepsis-induced myocardial injury (SIMI), a common complication of sepsis, may cause significant mortality. Ferroptosis, a cell death associated with oxidative stress and inflammation, has been identified to be involved in SIMI. This study sought to investigate the role of ANXA1 small peptide (ANXA1sp) in SIMI pathogenesis. In this study, the mouse cardiomyocytes (H9C2 cells) were stimulated with lipopolysaccharide (LPS) to imitate SIMI in vitro. It was shown that ANXA1sp treatment substantially abated LPS-triggered H9C2 cell death and excessive secretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). ANXA1sp pretreatment also reversed the increase of ROS and MDA generation as well as the decrease of SOD and GSH activity in H9C2 cells caused by LPS treatment. In addition, ANXA1sp considerably eliminated LPS-caused H9C2 cell ferroptosis, as revealed by the suppression of iron accumulation and the increase in GPX4 and FTH1 expression. Furthermore, the ameliorative effects of ANXA1sp on LPS-induced H9C2 cell damage could be partially abolished by erastin, a ferroptosis agonist. ANXA1sp enhanced SIRT3 expression in LPS-challenged H9C2 cells, thereby promoting p53 deacetylation. SIRT3 knockdown diminished ANXA1sp-mediated alleviation of cell death, inflammation, oxidative stress, and ferroptosis of LPS-treated H9C2 cells. Our study demonstrated that ANXA1sp is protected against LPS-induced cardiomyocyte damage by inhibiting ferroptosis-induced cell death via SIRT3-dependent p53 deacetylation, suggesting that ANXA1sp may be a potent therapeutic agent for SIMI.
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Affiliation(s)
- Song Qin
- Soochow University Medical College, Suzhou 215000, China
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Yingcong Ren
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Banghai Feng
- Department of Critical Care Medicine, Zunyi Hospital of Traditional Chinese Medicine, Zunyi, Guizhou 563000, China
| | - Xiaoqin Wang
- Department of Pediatric, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Junya Liu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Jie Zheng
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Kang Li
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Miao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Tao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Hong Mei
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xiaoyun Fu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
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Yin L, Tang Y, Lin X, Jiang B. Progress in the mechanism of mitochondrial dysfunction in septic cardiomyopathy. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2156622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Leijing Yin
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
| | - Yuting Tang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
| | - Xiaofang Lin
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
| | - Bimei Jiang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
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22
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Wang Z, Xiao D, Ji Q, Li Y, Cai Z, Fang L, Huo H, Zhou G, Yan X, Shen L, He B. Jujuboside A attenuates sepsis-induced cardiomyopathy by inhibiting inflammation and regulating autophagy. Eur J Pharmacol 2022; 947:175451. [PMID: 36502962 DOI: 10.1016/j.ejphar.2022.175451] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/02/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Jujuboside A (JuA), as a main effective component of Jujubogenin, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS). METHOD Wide type C57BL/6 mice and neonatal rat cardiomyocytes (NRCMs) were exposed to LPS to establish myocardial toxicity models. Cardiac function of septic mice was detected by echocardiography. Moreover, the survival rate was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detect the number of autophagosomes in myocardium. Finally, the expression of proteins related to pyroptosis, autophagy and oxidative stress was analyzed by western blotting and immunohistochemistry staining. RESULTS Results showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and pyroptosis; instead, it strengthened autophagy in SIC. Moreover, JuA also significantly decreased oxidative stress and nitrodative stress, as evidenced by suppressing the superoxide production and downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3-MA significantly abolished the effect of JuA on autophagic activity in SIC. CONCLUSION In conclusion, the findings indicated that JuA attenuates cardiac function via blocking inflammasome-mediated apoptosis and pyroptosis, at the same time by enhancing autophagy in SIC, heralding JuA as a potential therapy for sepsis.
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Tan Y, Xi D, Cai C, Jiang X, Chen S, Hu R, Xin T, Li Y, Wang S, Chang X, Zhou H. DUSP1 overexpression attenuates septic cardiomyopathy through reducing VCP phosphorylation and normalizing mitochondrial quality control. Acta Pharm Sin B 2022. [DOI: 10.1016/j.apsb.2022.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Singh J, Lee Y, Kellum JA. A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach. Crit Care 2022; 26:246. [PMID: 35962414 PMCID: PMC9373887 DOI: 10.1186/s13054-022-04075-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/23/2022] [Indexed: 11/30/2022] Open
Abstract
The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia–reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia–reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA “bed to bench” suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.
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Zou HX, Qiu BQ, Zhang ZY, Hu T, Wan L, Liu JC, Huang H, Lai SQ. Dysregulated autophagy-related genes in septic cardiomyopathy: Comprehensive bioinformatics analysis based on the human transcriptomes and experimental validation. Front Cardiovasc Med 2022; 9:923066. [PMID: 35983185 PMCID: PMC9378994 DOI: 10.3389/fcvm.2022.923066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/14/2022] [Indexed: 11/13/2022] Open
Abstract
Septic cardiomyopathy (SCM) is severe organ dysfunction caused by sepsis that is associated with poor prognosis, and its pathobiological mechanisms remain unclear. Autophagy is a biological process that has recently been focused on SCM, yet the current understanding of the role of dysregulated autophagy in the pathogenesis of SCM remains limited and uncertain. Exploring the molecular mechanisms of disease based on the transcriptomes of human pathological samples may bring the closest insights. In this study, we analyzed the differential expression of autophagy-related genes in SCM based on the transcriptomes of human septic hearts, and further explored their potential crosstalk and functional pathways. Key functional module and hub genes were identified by constructing a protein–protein interaction network. Eight key genes (CCL2, MYC, TP53, SOD2, HIF1A, CTNNB1, CAT, and ADIPOQ) that regulate autophagy in SCM were identified after validation in a lipopolysaccharide (LPS)-induced H9c2 cardiomyoblast injury model, as well as the autophagic characteristic features. Furthermore, we found that key genes were associated with abnormal immune infiltration in septic hearts and have the potential to serve as biomarkers. Finally, we predicted drugs that may play a protective role in SCM by regulating autophagy based on our results. Our study provides evidence and new insights into the role of autophagy in SCM based on human septic heart transcriptomes, which would be of great benefit to reveal the molecular pathological mechanisms and explore the diagnostic and therapeutic targets for SCM.
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Affiliation(s)
- Hua-Xi Zou
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bai-Quan Qiu
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ze-Yu Zhang
- Institute of Nanchang University Trauma Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Tie Hu
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Li Wan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ji-Chun Liu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Cardiovascular Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Huang Huang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Huang Huang,
| | - Song-Qing Lai
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Song-Qing Lai,
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Carbon monoxide-releasing molecule-2 ameliorates postresuscitation myocardial dysfunction in rat via mitochondrial-mediated apoptosis pathway and the regulation of mitochondrial dynamics. Eur J Pharmacol 2022; 927:175038. [DOI: 10.1016/j.ejphar.2022.175038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 12/11/2022]
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Acetyl-11-Keto- β-Boswellic Acid (AKBA) Prevents Lipopolysaccharide-Induced Inflammation and Cytotoxicity on H9C2 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2620710. [PMID: 35399644 PMCID: PMC8986374 DOI: 10.1155/2022/2620710] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/15/2022] [Indexed: 12/30/2022]
Abstract
Acetyl-11-keto-beta-boswellic acid (AKBA), the major component of Boswellia serrata, exhibits anti-inflammatory activities. This in vitro study investigated the protective effects of AKBA against lipopolysaccharide (LPS)-induced cardiac dysfunction. In this study, the H9C2 cardiomyocytes were pretreated with AKBA (2.5, 5, and 10 μM for 24 h), and then cotreated with LPS for another 24 h. The MTT assay, ELISA test kits, and quantitative real-time PCR analysis assessed the cell viability, levels of proinflammatory factors (IL-β, IL-6, TNF- α, and PGE2), and the gene expression of IL-β, IL-6, TNF- α, iNOS, and COX-2, respectively. The nitric oxide (NO) and thiol levels were also measured using a biochemical assay. The results indicated that LPS exposure markedly reduced cell viability and total thiol content, but increased the inflammatory cytokines, NO metabolites, and gene expression of proinflammatory mediators in H9C2 cells. AKBA pretreatment significantly altered the mentioned factors induced by LPS. Our results demonstrated that AKBA might be a promising therapeutic agent for treating sepsis-related cardiac dysfunction in the future.
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Zhu P, Chen Y, Wang J, Lin G, Wang R, Que Y, Zhou J, Xu G, Luo J, Du Y. Receptor-Interacting Protein Kinase 3 Suppresses Mitophagy Activation via the Yes-Associated Protein/Transcription Factor EB Pathways in Septic Cardiomyopathy. Front Cardiovasc Med 2022; 9:856041. [PMID: 35402535 PMCID: PMC8987354 DOI: 10.3389/fcvm.2022.856041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 02/16/2022] [Indexed: 11/13/2022] Open
Abstract
Mitophagy, known as the main mechanism of mitochondrial quality control, determines the pathophysiology of septic cardiomyopathy, although the precise regulatory mechanisms remain elusive. Data from the present study suggested that receptor-interacting protein kinase 3 (RIPK3) expression could be enhanced in response to lipopolysaccharide (LPS) challenge. Upregulated RIPK3 expression was accompanied by severe cardiac injury and cardiac dysfunction. Further examination revealed that elevated RIPK3 expression subsequently inhibited the Yes-associated protein (YAP) pathway, which was accompanied by reduced transcription factor EB (TFEB) expression. Inhibition of TFEB would reduce mitophagy, which ultimately induced cardiomyocyte death under LPS challenge. In contrast, loss of RIPK3 induced the YAP/TFEB/mitophagy pathway alleviated the sensitivity of cardiomyocytes to LPS-induced cytotoxicity. Collectively, the RIPK3/YAP/TFEB axis was confirmed to be responsible for the pathogenesis of septic cardiomyopathy by inhibiting mitophagy. These findings have potential significance for the progression of new approaches to the treatment of septic cardiomyopathy.
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Affiliation(s)
- Pingjun Zhu
- Department of Respiratory and Critical Care Medicine, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Yangxiaocao Chen
- Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
| | - Junyan Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Geng Lin
- The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Runsheng Wang
- Department of Respiratory and Critical Care Medicine, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Yifan Que
- The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Jin Zhou
- The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Guogang Xu
- The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Guogang Xu
| | - Jiang Luo
- The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- Jiang Luo
| | - Yingzhen Du
- Department of Disease Control and Prevention, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
- Yingzhen Du
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Zhu X, Sun M, Guo H, Lu G, Gu J, Zhang L, Shi L, Gao J, Zhang D, Wang W, Liu J, Wang X. Verbascoside protects from LPS-induced septic cardiomyopathy via alleviating cardiac inflammation, oxidative stress and regulating mitochondrial dynamics. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 233:113327. [PMID: 35203005 DOI: 10.1016/j.ecoenv.2022.113327] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/13/2022] [Accepted: 02/15/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Verbascoside (VB), as an active component of multiple medicinal plants, has been proved to exert anti-oxidative, anti-aging and neuroprotective effects. This study was designed to investigate whether VB could play a cardioprotective role in septic heart injury. METHODS Mice were injected with lipopolysaccharide (LPS; 10 mg/kg) to induce sepsis. The treatment group received an intraperitoneally injection of VB (20 mg/kg) before LPS challenge. Transthoracic echocardiography, ELISA, immunofluorescence, and qPCR were performed to assess the effect of VB on heart function, oxidative stress, inflammation and apoptosis. Transmission electronic microscopy and immunoblotting were used to evaluate the mitochondrial morphology and biogenesis of the septic heart. In vitro experiments were also performed to repeat above-mentioned assays. RESULTS Compared with LPS group, the VB treatment group showed improved cardiac function in sepsis. VB alleviated oxidative stress and inflammatory cell infiltration, as well as cardiomyocyte apoptosis. Specifically, VB could restore sepsis-induced mitochondrial alterations via regulating mitochondrial biogenesis. These results were also confirmed in in vitro experiments. CONCLUSION Verbascoside could protected from sepsis-induced cardiomyopathy by inhibiting oxidative stress, inflammation, and apoptosis, as well as promoting mitochondrial biogenesis.
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Affiliation(s)
- Xuanfeng Zhu
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Min Sun
- Hypertension Research Institute of Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Hongmei Guo
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Gan Lu
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Jianhua Gu
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Lingling Zhang
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Licheng Shi
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Jia Gao
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Dandan Zhang
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Wenjun Wang
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China
| | - Jiannan Liu
- Department of Respiratory Medicine, Geriatric Hospital of Nanjing Medical University; Jiangsu Province Official Hospital, Nanjing, China.
| | - Xia Wang
- Department of Geriatric Cardiology, Taian City Central Hospital, Taian, China.
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Wang X, Xie D, Dai H, Ye J, Liu Y, Fei A. Clemastine protects against sepsis-induced myocardial injury in vivo and in vitro. Bioengineered 2022; 13:7134-7146. [PMID: 35274595 PMCID: PMC9208445 DOI: 10.1080/21655979.2022.2047256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Sepsis-induced myocardial dysfunction (SIMD) is associated with high morbidity and mortality rates; however, it lacks targeted therapies. Modulating cardiomyocyte autophagy maintains intracellular homeostasis during SIMD. Clemastine, a histamine receptor inhibitor, promotes autophagy and other effective biological functions. Nevertheless, the effect of clemastine on SIMD remains unclear. This study aimed to explore the underlying mechanism of clemastine in cardiomyocyte injury in cecum ligation and perforation (CLP)-induced rats and lipopolysaccharide (LPS)-stimulated H9c2 cells. Clemastine (10 mg/kg, 30 mg/kg, and 50 mg/kg) was intraperitoneally injected after 30 min of CLP surgery. Serum cTnI levels and the 7-day survival rate were evaluated. Echocardiograms and H&E staining were used to evaluate cardiac function and structure. TEM was used to detect the mitochondrial ultrastructure and autophagosomes. Clemastine significantly improved the survival rate and reduced cTnI production in serum. Clemastine ameliorated cellular apoptosis, improved mitochondrial ultrastructure both in vivo and in vitro, increased ATP content, decreased dynamin-related protein 1 (DRP1) expression, and decreased mitochondrial ROS levels. Additionally, clemastine treatment increased autophagosome concentration, LC3II/LC3I rate, and Beclin 1 expression. However, 3-methyladenine (3-MA), an autophagy inhibitor, could abolish the effect of clemastine on alleviating myocardial apoptosis. In conclusion, clemastine protected against cardiac structure destruction and function dysfunction, mitochondrial damage, apoptosis, and autophagy in vivo and in vitro. Moreover, clemastine attenuated myocardial apoptosis by promoting autophagy. This study provides a novel favorable perspective for SIMD therapy.
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Affiliation(s)
- Xiaowan Wang
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Di Xie
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hui Dai
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiawei Ye
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuqi Liu
- Department of General Practice, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Aihua Fei
- Department of General Practice, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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Lorente L, Gómez-Bernal F, Martín M, Navarro-Gonzálvez J, Argueso M, Perez A, Ramos-Gómez L, Solé-Violán J, Marcos y Ramos J, Ojeda N, Jiménez A. High serum nitrates levels in non-survivor COVID-19 patients. MEDICINA INTENSIVA (ENGLISH EDITION) 2022; 46:132-139. [PMID: 35221002 PMCID: PMC8867537 DOI: 10.1016/j.medine.2020.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/25/2020] [Indexed: 02/07/2023]
Abstract
Objective Higher blood nitrate and nitrite levels have been found in coronavirus disease 2019 (COVID-19) patients than in healthy subjects. The present study explores the potential association between serum nitrate levels and mortality in COVID-19 patients. Design A prospective observation study was carried out. Setting Eight Intensive Care Units (ICUs) from 6 hospitals in the Canary Islands (Spain). Patients COVID-19 patients admitted to the ICU. Interventions Determination of serum nitrate levels at ICU admission. Main variable of interest Mortality at 30 days. Results Non-surviving (n = 11) compared to surviving patients (n = 42) showed higher APACHE-II (p < 0.001) and SOFA scores (p = 0.004), and higher serum nitrate levels (p = 0.001). Logistic regression analyses showed serum nitrate levels to be associated to 30-day mortality after controlling for SOFA (OR = 1.021; 95%CI = 1.006–1.036; p = 0.01) or APACHE-II (OR = 1.023; 95%CI = 1.006–1.041; p = 0.01). There were no differences in the area under the curve (AUC) for mortality prediction by serum nitrate levels (AUC = 83%; 95%CI = 73–92%; p < 0.001), APACHE II (AUC = 85%; 95%CI = 75–96%; p < 0.001) and SOFA (AUC = 78%; 95%CI = 63–92%; p = 0.005) based on the DeLong method. The Kaplan–Meier analysis found patients with serum nitrates levels > 68.4 μmol/l to have a higher mortality rate (hazard ratio = 138.8; 95%CI = 22.3–863.9; p < 0.001). Conclusions The main novel finding was the association between serum nitrate levels and mortality in COVID-19 patients controlling for the SOFA or APACHE-II scores, though larger studies are needed to confirm this observation.
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The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases. Int J Mol Sci 2022; 23:ijms23020952. [PMID: 35055137 PMCID: PMC8778138 DOI: 10.3390/ijms23020952] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/08/2022] [Accepted: 01/14/2022] [Indexed: 02/01/2023] Open
Abstract
Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the development and progression of some CVD. Moreover, specific types of mitochondria-mediated CVD have been discovered, such as MIEH (maternally inherited essential hypertension) and maternally inherited CHD (coronary heart disease). Maternally inherited mitochondrial CVD is caused by certain mutations in the mtDNA, which encode structural mitochondrial proteins and mitochondrial tRNA. In this review, we focus on recently identified mtDNA mutations associated with CVD (coronary artery disease and hypertension). Additionally, new data suggest the role of mtDNA mutations in Brugada syndrome and ischemic stroke, which before were considered only as a result of mutations in nuclear genes. Moreover, we discuss the molecular mechanisms of mtDNA involvement in the development of the disease.
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Boissier F, Aissaoui N. Septic cardiomyopathy: Diagnosis and management. JOURNAL OF INTENSIVE MEDICINE 2021; 2:8-16. [PMID: 36789232 PMCID: PMC9923980 DOI: 10.1016/j.jointm.2021.11.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 11/14/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022]
Abstract
There is an extensive body of literature focused on sepsis-induced myocardial dysfunction, but results are conflicting and no objective definition of septic cardiomyopathy (SCM) has been established. SCM may be defined as a sepsis-associated acute syndrome of non-ischemic cardiac dysfunction with systolic and/or diastolic left ventricular (LV) dysfunction and/or right ventricular dysfunction. Physicians should consider this diagnosis in patients with sepsis-associated organ dysfunction, and particularly in cases of septic shock that require vasopressors. Echocardiography is currently the gold standard for diagnosis of SCM. Left ventricular ejection fraction is the most common parameter used to describe LV function in the literature, but its dependence on loading conditions, particularly afterload, limits its use as a measure of intrinsic myocardial contractility. Therefore, repeated echocardiography evaluation is mandatory. Evaluation of global longitudinal strain (GLS) may be more sensitive and specific for SCM than LV ejection fraction (LVEF). Standard management includes etiological treatment, adapted fluid resuscitation, use of vasopressors, and monitoring. Use of inotropes remains uncertain, and heart rate control could be an option in some patients.
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Affiliation(s)
- Florence Boissier
- Service de Médecine Intensive Réanimation, CHU de Poitiers, Poitiers 86021, France,Université de Poitiers, Poitiers INSERM CIC 1402 (ALIVE group), France
| | - Nadia Aissaoui
- Service de Médecine Intensive Réanimation, Hôpital Cochin, APHP, Paris 75014, France,Université de Paris, Paris Cardiovascular Research Center, INSERM U970, Paris 75015, France,Corresponding author: Nadia Aissaoui, Service de Médecine Intensive–Réanimation, Hôpital Cochin Assistance Publique–Hôpitaux de Paris, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France.
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The Anti-Inflammatory and Antiapoptotic Effects of Nicorandil in Antisepsis Cardiomyopathy. Cardiovasc Ther 2021; 2021:5822920. [PMID: 34950238 PMCID: PMC8668340 DOI: 10.1155/2021/5822920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 11/04/2021] [Accepted: 11/16/2021] [Indexed: 11/30/2022] Open
Abstract
Objective To observe the effect of nicorandil on septic rats and explore the possible mechanism of its myocardial protection, so as to provide theoretical basis for the treatment of septic cardiomyopathy. Methods Sixty male clean SD rats were selected as the research objects and randomly divided into 3 groups by random number method: sham operation group (sham group), cecal ligation and perforation group (CLP group), nicorandil treatment group (nicorandil+CLP group). After the operation, the nicorandil group was pumped with nicorandil diluent 1 ml/h (2 mg/kg/h) with a micropump for 6 hours. The sham group and CLP group were pumped with the same amount of normal saline 1 ml/h for a total of 6 hours. After 24 hours, the survival of the rats in each group was observed. The expression of troponin I (cTnI), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) in the serum was detected. Then, the ventricle was harvested for the observation of the pathological changes of myocardium. Quantitative real-time polymerase chain reaction and immunostaining were used to detect myocardial tissue apoptosis, and Western blot methods were used to detect protein expression changes in nuclear factor-κB (NF-κB) pathways. Results 24 hours after operation, the survival rate of the rats in the CLP group was 60%. There was a large amount of necrosis of myocardial cells and inflammatory cell infiltration. The survival rate of rats in the nicorandil+CLP group was 75%. Compared with the CLP group, the necrosis of myocardial cells was reduced, and there was still a small amount of inflammatory cell infiltration. In the CLP group, myocardial inflammation and apoptosis were significant, and NF-κB pathway was activated. On the contrary, the NF-κB pathway in the nicorandil+CLP group was inhibited, and the expression of inflammatory factors and apoptosis factors was inhibited. Conclusion Nicorandil can reduce the release of inflammatory factors in septic rats, improve the inflammatory response, reduce myocardial damage, and play a myocardial protective effect. Its mechanism may be related to the inhibition of the activation of NF-κB signaling pathway.
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Liu S, Chong W. Roles of LncRNAs in Regulating Mitochondrial Dysfunction in Septic Cardiomyopathy. Front Immunol 2021; 12:802085. [PMID: 34899764 PMCID: PMC8652231 DOI: 10.3389/fimmu.2021.802085] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 11/10/2021] [Indexed: 01/20/2023] Open
Abstract
Sepsis is an abnormal systemic inflammatory response of the host immune system to infection and can lead to fatal multiorgan dysfunction syndrome. Epidemiological studies have shown that approximately 10-70% of sepsis cases can lead to septic cardiomyopathy. Since the pathogenesis of septic cardiomyopathy is not clear, it is difficult for medical doctors to treat the disease. Therefore, finding effective interventions to prevent and reduce myocardial damage in septic cardiomyopathy is clinically significant. Epigenetics is the study of stable genetic phenotype inheritance that does not involve changing gene sequences. Epigenetic inheritance is affected by both gene and environmental regulation. Epigenetic studies focus on the modification and influence of chromatin structure, mainly including chromatin remodelling, DNA methylation, histone modification and noncoding RNA (ncRNA)-related mechanisms. Recently, long ncRNA (lncRNA)-related mechanisms have been the focus of epigenetic studies. LncRNAs are expected to become important targets to prevent, diagnose and treat human diseases. As the energy metabolism centre of cells, mitochondria are important targets in septic cardiomyopathy. Intervention measures to prevent and treat mitochondrial damage are of great significance for improving the prognosis of septic cardiomyopathy. LncRNAs play important roles in life activities. Recently, studies have focused on the involvement of lncRNAs in regulating mitochondrial dysfunction. However, few studies have revealed the involvement of lncRNAs in regulating mitochondrial dysfunction in septic cardiomyopathy. In this article, we briefly review recent research in this area.
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Affiliation(s)
- Shuang Liu
- Department of Emergency, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Wei Chong
- Department of Emergency, The First Affiliated Hospital of China Medical University, Shenyang, China
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Zhang YY, Ning BT. Signaling pathways and intervention therapies in sepsis. Signal Transduct Target Ther 2021; 6:407. [PMID: 34824200 PMCID: PMC8613465 DOI: 10.1038/s41392-021-00816-9] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/19/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection. Over decades, advanced understanding of host-microorganism interaction has gradually unmasked the genuine nature of sepsis, guiding toward new definition and novel therapeutic approaches. Diverse clinical manifestations and outcomes among infectious patients have suggested the heterogeneity of immunopathology, while systemic inflammatory responses and deteriorating organ function observed in critically ill patients imply the extensively hyperactivated cascades by the host defense system. From focusing on microorganism pathogenicity, research interests have turned toward the molecular basis of host responses. Though progress has been made regarding recognition and management of clinical sepsis, incidence and mortality rate remain high. Furthermore, clinical trials of therapeutics have failed to obtain promising results. As far as we know, there was no systematic review addressing sepsis-related molecular signaling pathways and intervention therapy in literature. Increasing studies have succeeded to confirm novel functions of involved signaling pathways and comment on efficacy of intervention therapies amid sepsis. However, few of these studies attempt to elucidate the underlining mechanism in progression of sepsis, while other failed to integrate preliminary findings and describe in a broader view. This review focuses on the important signaling pathways, potential molecular mechanism, and pathway-associated therapy in sepsis. Host-derived molecules interacting with activated cells possess pivotal role for sepsis pathogenesis by dynamic regulation of signaling pathways. Cross-talk and functions of these molecules are also discussed in detail. Lastly, potential novel therapeutic strategies precisely targeting on signaling pathways and molecules are mentioned.
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Affiliation(s)
- Yun-Yu Zhang
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Bo-Tao Ning
- Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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Xu L, Wu XM, Zhang YK, Huang MJ, Chen J. Simvastatin inhibits the inflammation and oxidative stress of human neutrophils in sepsis via autophagy induction. Mol Med Rep 2021; 25:25. [PMID: 34812477 DOI: 10.3892/mmr.2021.12541] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 10/11/2021] [Indexed: 11/06/2022] Open
Abstract
Simvastatin exerts a protective effect during sepsis (SP) in animal models; however, the underlying mechanism is not completely understood, particularly in human SP. Neutrophils are a critical effector in the host inflammatory response to SP. Therefore, the present study aimed to investigate the effect of simvastatin on neutrophils in human SP. Neutrophils were isolated from the peripheral venous blood of adult patients with SP and healthy volunteers (HP). Cell viability was analyzed using the MTT assay. Intracellular reactive oxygen species (ROS) generation and the concentrations of inflammatory mediators were also assessed using flow cytometry and ELISA. The results demonstrated that the cell viability of neutrophils from the SP group was significantly decreased compared with that in the HP group, and that treatment with simvastatin partly reversed the reduced cell viability. Furthermore, simvastatin administration significantly decreased ROS production and the concentrations of TNF‑α and IL‑6, which were significantly increased in neutrophils isolated from the SP group. Simvastatin also enhanced autophagy induction, as indicated by the promotion of the conversion of LC3I to LC3II and the increased expression levels of Beclin 1 in SP neutrophils. Treatment with 3‑methyladenine, an autophagy inhibitor, completely blocked the protective effects of simvastatin on neutrophils from SP, including the effects of simvastatin on the inhibition of inflammation, oxidative stress and improving cell viability. Collectively, the present study provided evidence for the simvastatin‑induced autophagic process of neutrophils involved in human SP, which protects neutrophils and partially attenuates the inflammatory response and oxidative stress. Therefore, the augmentation of neutrophil autophagy may serve as a potential therapeutic target for patients with SP.
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Affiliation(s)
- Li Xu
- Intensive Care Unit, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xiao-Min Wu
- Intensive Care Unit, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yu-Kun Zhang
- Intensive Care Unit, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ming-Jie Huang
- Intensive Care Unit, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jun Chen
- Intensive Care Unit, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Wasyluk W, Nowicka-Stążka P, Zwolak A. Heart Metabolism in Sepsis-Induced Cardiomyopathy-Unusual Metabolic Dysfunction of the Heart. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18147598. [PMID: 34300048 PMCID: PMC8303349 DOI: 10.3390/ijerph18147598] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/26/2021] [Accepted: 07/02/2021] [Indexed: 12/11/2022]
Abstract
Due to the need for continuous work, the heart uses up to 8% of the total energy expenditure. Due to the relatively low adenosine triphosphate (ATP) storage capacity, the heart's work is dependent on its production. This is possible due to the metabolic flexibility of the heart, which allows it to use numerous substrates as a source of energy. Under normal conditions, a healthy heart obtains approximately 95% of its ATP by oxidative phosphorylation in the mitochondria. The primary source of energy is fatty acid oxidation, the rest of the energy comes from the oxidation of pyruvate. A failed heart is characterised by a disturbance in these proportions, with the contribution of individual components as a source of energy depending on the aetiology and stage of heart failure. A unique form of cardiac dysfunction is sepsis-induced cardiomyopathy, characterised by a significant reduction in energy production and impairment of cardiac oxidation of both fatty acids and glucose. Metabolic disorders appear to contribute to the pathogenesis of cardiac dysfunction and therefore are a promising target for future therapies. However, as many aspects of the metabolism of the failing heart remain unexplained, this issue requires further research.
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Affiliation(s)
- Weronika Wasyluk
- Chair of Internal Medicine and Department of Internal Medicine in Nursing, Faculty of Health Sciences, Medical University of Lublin, 20-093 Lublin, Poland; (P.N.-S.); (A.Z.)
- Doctoral School, Medical University of Lublin, 20-093 Lublin, Poland
- Correspondence:
| | - Patrycja Nowicka-Stążka
- Chair of Internal Medicine and Department of Internal Medicine in Nursing, Faculty of Health Sciences, Medical University of Lublin, 20-093 Lublin, Poland; (P.N.-S.); (A.Z.)
| | - Agnieszka Zwolak
- Chair of Internal Medicine and Department of Internal Medicine in Nursing, Faculty of Health Sciences, Medical University of Lublin, 20-093 Lublin, Poland; (P.N.-S.); (A.Z.)
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Preau S, Vodovar D, Jung B, Lancel S, Zafrani L, Flatres A, Oualha M, Voiriot G, Jouan Y, Joffre J, Huel F, De Prost N, Silva S, Azabou E, Radermacher P. Energetic dysfunction in sepsis: a narrative review. Ann Intensive Care 2021; 11:104. [PMID: 34216304 PMCID: PMC8254847 DOI: 10.1186/s13613-021-00893-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Background Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies. Supplementary Information The online version contains supplementary material available at 10.1186/s13613-021-00893-7.
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Affiliation(s)
- Sebastien Preau
- U1167 - RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, F-59000, Lille, France.
| | - Dominique Vodovar
- Centre AntiPoison de Paris, Hôpital Fernand Widal, APHP, 75010, Paris, France.,Faculté de pharmacie, UMRS 1144, 75006, Paris, France.,Université de Paris, UFR de Médecine, 75010, Paris, France
| | - Boris Jung
- Medical Intensive Care Unit, Lapeyronie Teaching Hospital, Montpellier University Hospital and PhyMedExp, University of Montpellier, Montpellier, France
| | - Steve Lancel
- U1167 - RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, F-59000, Lille, France
| | - Lara Zafrani
- Médecine Intensive Réanimation, Hôpital Saint-Louis, AP-HP, Université de Paris, Paris, France.,INSERM UMR 976, Hôpital Saint Louis, Université de Paris, Paris, France
| | | | - Mehdi Oualha
- Pediatric Intensive Care Unit, Necker Hospital, APHP, Centre - Paris University, Paris, France
| | - Guillaume Voiriot
- Service de Médecine Intensive Réanimation, Sorbonne Université, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, Paris, France
| | - Youenn Jouan
- Service de Médecine Intensive Réanimation, CHRU Tours, Tours, France.,Faculté de Médecine de Tours, INSERM U1100 Centre d'Etudes des Pathologies Respiratoires, Tours, France
| | - Jeremie Joffre
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, 94143, USA
| | - Fabrice Huel
- Réanimation médico-chirurgicale, Université de Paris, Assistance Publique - Hôpitaux de Paris, Hôpital Louis Mourier, Paris, France
| | - Nicolas De Prost
- Service de Réanimation Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Cedex 94010, Créteil, France
| | - Stein Silva
- Réanimation URM CHU Purpan, Cedex 31300, Toulouse, France.,Toulouse NeuroImaging Center INSERM1214, Cedex 31300, Toulouse, France
| | - Eric Azabou
- Clinical Neurophysiology and Neuromodulation Unit, Departments of Physiology and Critical Care Medicine, Raymond Poincaré Hospital, AP-HP, Inserm UMR 1173, Infection and Inflammation (2I), University of Versailles (UVSQ), Paris-Saclay University, Paris, France
| | - Peter Radermacher
- Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Ulm, Germany
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Wang Z, Liu M, Ye D, Ye J, Wang M, Liu J, Xu Y, Zhang J, Zhao M, Feng Y, Xu S, Pan W, Luo Z, Li D, Wan J. Il12a Deletion Aggravates Sepsis-Induced Cardiac Dysfunction by Regulating Macrophage Polarization. Front Pharmacol 2021; 12:632912. [PMID: 34276358 PMCID: PMC8284189 DOI: 10.3389/fphar.2021.632912] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiac dysfunction is a well-recognized complication of sepsis and is associated with the outcome and prognosis of septic patients. Evidence suggests that Il12a participates in the regulation of various cardiovascular diseases, including heart failure, hypertension and acute myocardial infarction. However, the effects of Il12a in sepsis-induced cardiac dysfunction remain unknown. In our study, lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) model were used to mimic sepsis, and cardiac Il12a expression was assessed. In addition, Il12a knockout mice were used to detect the role of Il12a in sepsis-related cardiac dysfunction. We observed for the first time that Il12a expression is upregulated in mice after LPS treatment and macrophages were the main sources of Il12a. In addition, our findings demonstrated that Il12a deletion aggravates LPS-induced cardiac dysfunction and injury, as evidenced by the increased serum and cardiac levels of lactate dehydrogenase (LDH) and cardiac creatine kinase-myocardial band (CK-MB). Moreover, Il12a deletion enhances LPS-induced macrophage accumulation and drives macrophages toward the M1 phenotype in LPS-treated mice. Il12a deletion also downregulated the activity of AMP-activated protein kinase (AMPK) but increased the phosphorylation levels of p65 (p-p65) and NF-κB inhibitor alpha (p-IκBα). In addition, Il12a deletion aggravates CLP-induced cardiac dysfunction and injury. Treatment with the AMPK activator AICAR abolishes the deterioration effect of Il12a deletion on LPS-induced cardiac dysfunction. In conclusion, Il12a deletion aggravated LPS-induced cardiac dysfunction and injury by exacerbating the imbalance of M1 and M2 macrophages. Our data provide evidence that Il12a may represent an attractive target for sepsis-induced cardiac dysfunction.
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Affiliation(s)
- Zhen Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Menglin Liu
- Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, China
| | - Di Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jing Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mengmeng Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yongqi Feng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Shuwan Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Wei Pan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zhen Luo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Dan Li
- Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
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Tan Y, Wan HH, Sun MM, Zhang WJ, Dong M, Ge W, Ren J, Peng H. Cardamonin protects against lipopolysaccharide-induced myocardial contractile dysfunction in mice through Nrf2-regulated mechanism. Acta Pharmacol Sin 2021; 42:404-413. [PMID: 32317756 PMCID: PMC8027872 DOI: 10.1038/s41401-020-0397-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/15/2020] [Indexed: 12/29/2022]
Abstract
In patients with sepsis, lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria triggers cardiac dysfunction and heart failure, but target therapy for septic cardiomyopathy remains unavailable. In this study we evaluated the beneficial effects of cardamonin (CAR), a flavone existing in Alpinia plant, on endotoxemia-induced cardiac dysfunction and the underlying mechanisms with focus on oxidative stress and apoptosis. Adult mice were exposed to LPS (4 mg/kg, i.p. for 6 h) prior to functional or biochemical assessments. CAR (20 mg/kg, p.o.) was administered to mice immediately prior to LPS challenge. We found that LPS challenge compromised cardiac contractile function, evidenced by compromised fractional shortening, peak shortening, maximal velocity of shortening/relengthening, enlarged LV end systolic diameter and prolonged relengthening in echocardiography, and induced apoptosis, overt oxidative stress (O2- production and reduced antioxidant defense) associated with inflammation, phosphorylation of NF-κB and cytosolic translocation of transcriptional factor Nrf2. These deteriorative effects were greatly attenuated or mitigated by CAR administration. However, H&E and Masson's trichrome staining analysis revealed that neither LPS challenge nor CAR administration significantly affected cardiomyocyte cross-sectional area and interstitial fibrosis. Mouse cardiomyocytes were treated with LPS (4 µg/mL) for 6 h in the absence or presence of CAR (10 μM) in vitro. We found that addition of CAR suppressed LPS-induced defect in cardiomyocyte shortening, which was nullified by the Nrf2 inhibitor ML-385 or the NF-κB activator prostratin. Taken together, our results suggest that CAR administration protects against LPS-induced cardiac contractile abnormality, oxidative stress, apoptosis, and inflammation through Nrf2- and NF-κB-dependent mechanism.
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Affiliation(s)
- Ying Tan
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Hong-Hong Wan
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Ming-Ming Sun
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Wen-Jing Zhang
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Maolong Dong
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
| | - Wei Ge
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
- Department of General Practice, Xijing Hospital, the Air Force Military Medical University, Xi'an, 710032, China.
| | - Jun Ren
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
| | - Hu Peng
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Mao JY, Su LX, Li DK, Zhang HM, Wang XT, Liu DW. The effects of UCP2 on autophagy through the AMPK signaling pathway in septic cardiomyopathy and the underlying mechanism. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:259. [PMID: 33708886 PMCID: PMC7940903 DOI: 10.21037/atm-20-4819] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background Mitochondrial dysfunction plays an important role in the development of septic cardiomyopathy. This study aimed to reveal the protective role of uncoupling protein 2 (UCP2) in mitochondria through AMP-activated protein kinase (AMPK) on autophagy during septic cardiomyopathy. Methods UCP2 knockout mice via a cecal ligation and puncture (CLP) model and the H9C2 cardiomyocyte cell line in response to lipopolysaccharide (LPS) in vitro were used to study the effect. The myocardial morphological alterations, indicators of mitochondrial injury and levels of autophagy-associated proteins (pAMPK, pmTOR, pULK1, pTSC2, Beclin-1, and LC3-I/II) were assessed. In addition, the mechanism of the interaction between UCP2 and AMPK was further studied through gain- and loss-of-function studies. Results Compared with the wild-type mice, the UCP2 knockout mice exhibited more severe cardiomyocyte injury after CLP, and the AMPK agonist AICAR protected against such injury. Consistent with this result, silencing UCP2 augmented the LPS-induced pathological damage and mitochondrial injury in the H9C2 cells, limited the upregulation of autophagy proteins and reduced AMPK phosphorylation. AICAR protected the cells from morphological changes and mitochondrial membrane potential loss and promoted autophagy. The silencing and overexpression of UCP2 led to correlated changes in the AMPK upstream kinases pLKB1 and CAMKK2. Conclusions UCP2 exerts cardioprotective effects on mitochondrial dysfunction during sepsis via the action of AMPK on autophagy.
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Affiliation(s)
- Jia-Yu Mao
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Long-Xiang Su
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Dong-Kai Li
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Hong-Min Zhang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Xiao-Ting Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Da-Wei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
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Zhao S, Chen F, Yin Q, Wang D, Han W, Zhang Y. Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression. Front Physiol 2020; 11:571810. [PMID: 33324236 PMCID: PMC7723971 DOI: 10.3389/fphys.2020.571810] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022] Open
Abstract
Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.
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Affiliation(s)
- Shuai Zhao
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
| | - Fan Chen
- Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany
| | - Qiliang Yin
- Department of Oncology, First Hospital of Jilin University, Changchun, China
| | - Dunwei Wang
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
| | - Wei Han
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
| | - Yuan Zhang
- Department of Anesthesiology, First Hospital of Jilin University, Changchun, China
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Wang W, Xu H, Lin H, Molnar M, Ren H. The role of the cholinergic anti-inflammatory pathway in septic cardiomyopathy. Int Immunopharmacol 2020; 90:107160. [PMID: 33243604 DOI: 10.1016/j.intimp.2020.107160] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 12/30/2022]
Abstract
Septic cardiomyopathy (SCM)is common in septic patients and results in cardiovascular failure. The pathogenesis of SCM is complicated, and patients with SCM have high mortality because current treatment methods are limited. The cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through vagus nerve stimulation that leads to the release of acetylcholine (ACh), which binds to the alpha7 nicotinic acetylcholine receptor (α7nAChR). Moreover, α7nAChR activation by its agonists at the tissue level inhibits inflammatory mediators and regulates the function of immune cells in sepsis. Therefore, the α7nAChR can maintain balance of the inflammatory-immune response in sepsis. CAP has been elucidated as a critical regulator of anti-inflammation in many diseases, including rheumatoid arthritis, inflammatory boweldisease and SCM. Additionally, some clinical and preclinical trials show therapeutic potential via regulating CAP. There are excellent studies regarding the beneficial role of CAP activation, especially α7nAChR, in experimental SCM. This review aims to discuss the CAP in attenuating inflammation and the potential role of α7nAChR activation in regulating immune and reducing inflammation in SCM.
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Affiliation(s)
- Wenting Wang
- Department of Intensive Care Unit, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Hui Xu
- Department of Intensive Care Unit, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Huan Lin
- Department of Intensive Care Unit, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Megan Molnar
- College of Medicine, SUNY Upstate Medical University, Syracuse, USA.
| | - Hongsheng Ren
- Department of Intensive Care Unit, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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Lorente L, Gómez-Bernal F, Martín MM, Navarro-Gonzálvez JA, Argueso M, Perez A, Ramos-Gómez L, Solé-Violán J, Marcos Y Ramos JA, Ojeda N, Jiménez A. High serum nitrates levels in non-survivor COVID-19 patients. Med Intensiva 2020; 46:S0210-5691(20)30336-3. [PMID: 33293102 PMCID: PMC7654288 DOI: 10.1016/j.medin.2020.10.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/13/2020] [Accepted: 10/25/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Higher blood nitrate and nitrite levels have been found in coronavirus disease 2019 (COVID-19) patients than in healthy subjects. The present study explores the potential association between serum nitrate levels and mortality in COVID-19 patients. DESIGN A prospective observation study was carried out. SETTING Eight Intensive Care Units (ICUs) from 6 hospitals in the Canary Islands (Spain). PATIENTS COVID-19 patients admitted to the ICU. INTERVENTIONS Determination of serum nitrate levels at ICU admission. MAIN VARIABLE OF INTEREST Mortality at 30 days. RESULTS Non-surviving (n=11) compared to surviving patients (n=42) showed higher APACHE-II (p<0.001) and SOFA scores (p=0.004), and higher serum nitrate levels (p=0.001). Logistic regression analyses showed serum nitrate levels to be associated to 30-day mortality after controlling for SOFA (OR=1.021; 95%CI=1.006-1.036; p=0.01) or APACHE-II (OR=1.023; 95%CI=1.006-1.041; p=0.01). There were no differences in the area under the curve (AUC) for mortality prediction by serum nitrate levels (AUC=83%; 95%CI=73-92%; p<0.001), APACHE II (AUC=85%; 95%CI=75-96%; p<0.001) and SOFA (AUC=78%; 95%CI=63-92%; p=0.005) based on the DeLong method. The Kaplan-Meier analysis found patients with serum nitrates levels>68.4μmol/l to have a higher mortality rate (hazard ratio=138.8; 95%CI=22.3-863.9; p<0.001). CONCLUSIONS The main novel finding was the association between serum nitrate levels and mortality in COVID-19 patients controlling for the SOFA or APACHE-II scores, though larger studies are needed to confirm this observation.
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Affiliation(s)
- L Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain.
| | - F Gómez-Bernal
- Laboratory Department, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - M M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - J A Navarro-Gonzálvez
- Laboratory Department, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - M Argueso
- Intensive Care Unit, Complejo Hospitalario Universitario Insular, Las Palmas de Gran Canaria, Spain
| | - A Perez
- Internal Intensive Care Unit, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
| | - L Ramos-Gómez
- Intensive Care Unit, Hospital General La Palma, Breña Alta, Santa Cruz de Tenerife, Spain
| | - J Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - J A Marcos Y Ramos
- Intensive Care Unit, Hospital Doctor José Molina Orosa, Arrecife, Las Palmas, Spain
| | - N Ojeda
- Department of Anesthesiology, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
| | - A Jiménez
- Research Unit, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain
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Li Y, Feng YF, Liu XT, Li YC, Zhu HM, Sun MR, Li P, Liu B, Yang H. Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis. Redox Biol 2020; 38:101771. [PMID: 33189984 PMCID: PMC7674615 DOI: 10.1016/j.redox.2020.101771] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/04/2020] [Accepted: 10/23/2020] [Indexed: 02/09/2023] Open
Abstract
Septic cardiomyopathy is characterized by impaired contractive function with mitochondrial dysregulation. Songorine is a typical active C20-diterpene alkaloid from the lateral root of Aconitum carmichaelii, which has been used for the treatment of heart failure. This study investigated the protective role of songorine in septic heart injury from the aspect of mitochondrial biogenesis. Songorine (10, 50 mg/kg) protected cardiac contractive function against endotoxin insult in mice with Nrf2 induction. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial reactive oxygen species (ROS) production and redistributed STIM1 to interact with Orai1 for the formation of calcium release-activated calcium (CRAC) channels, mediating calcium influx, which were prevented by songorine, likely due to ROS suppression. Songorine activated Nrf2 by promoting Keap1 degradation, having a contribution to enhancing antioxidant defenses. When LPS shifted metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) in cardiomyocytes, songorine upregulated mitochondrial genes involved in fatty acid β-oxidation, tricarboxylic acid (TCA) cycle and electron transport chain in a manner dependent on Nrf2, resultantly protecting the capability of OXPHOS. Songorine increased luciferase report gene activities of nuclear respiratory factor-1 (Nrf1) and mitochondrial transcription factor A (Tfam) dependently on Nrf2, indicative of the regulation of Nrf2/ARE and NRF1 signaling cascades. Songorine promoted PGC-1α binding to Nrf2, and the cooperation was required for songorine to activate Nrf2/ARE and NRF1 for the control of mitochondrial quality and quantity. In support, the beneficial effects of songorine on cardioprotection and mitochondrial biogenesis were diminished by cardiac Nrf2 deficiency in mice subjected to LPS challenge. Taken together, these results showed that Nrf2 transcriptionally promoted mitochondrial biogenesis in cooperation with PGC-1α. Songorine activated Nrf2/ARE and NRF1 signaling cascades to rescue cardiomyocytes from endotoxin insult, suggesting that protection of mitochondrial biogenesis was a way for pharmacological intervention to prevent septic heart injury.
Mitochondrial ROS increased calcium influx through CRAC channels. Nrf2 interacted with PGC-1α to regulate mitochondrial biogenesis. Songorine activated Nrf2 by promoting Keap1 degradation. Songorine regulated Nrf2/ARE and PGC-1α cascades to protect cardiac function.
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Affiliation(s)
- Yi Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Yu-Fan Feng
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Xiao-Tian Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Yu-Chen Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Hui-Min Zhu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Meng-Ru Sun
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Baolin Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Hua Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
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Zhang D, Zhang Q, Zheng Y, Lu J. Anti-breast cancer and toxicity studies of total secondary saponin from Anemone raddeana Rhizome on MCF-7 cells via ROS generation and PI3K/AKT/mTOR inactivation. JOURNAL OF ETHNOPHARMACOLOGY 2020; 259:112984. [PMID: 32446927 DOI: 10.1016/j.jep.2020.112984] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/01/2020] [Accepted: 05/14/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The rhizome of Anemone raddeana Regel (A. raddeana) is a famous traditional Chinese medicine (TCM) recorded in Chinese Pharmacopoeia for the treatment of carbuncle and swelling. Carbuncle swollen is an explanation of tumor in the theory of TCM and softening and resolving hard mass effects are one of the important pharmacological activities of A. raddeana. AIM OF THE STUDY We investigated the potential anti-breast cancer effect and toxicological properties of alkali-ethanol extract from A. raddeana, namely total secondary saponin (TSS). MATERIALS AND METHODS Anti-proliferative effect of total saponin of A. raddeana (ATS) and TSS were tested using MTT assay. Hoechst staining, flow cytometry analysis, DCFH-DA fluorescence microscopy and western blot were carried out to evaluate the mechanisms of action of TSS. The potential anti-breast cancer activity and toxicological properties of TSS were tested in vivo. RESULTS ATS and TSS could inhibit the proliferation of A549, HepG2, MCF-7, MDA-MB-231 and SKBr-3 cells, especially for MCF-7 cells. Flow cytometry analysis revealed that TSS (10, 12 and 15 μg/ml) could induce cell cycle arrest on G0/G1 phase and promote apoptosis of MCF-7 cells. TSS could increase Bax/Bcl-2 ratio, elevate cytochrome c levels in cytosol and activate caspase-3/9. In addition, TSS also induced ROS generation and inactivated PI3K/AKT/mTOR pathway which may involved in the mitochondrial dysfunction of MCF-7 cells. TSS showed slight toxic at the dosage of 100 and 200 mg/kg by oral administration without any toxic potential for 28 days. TSS (50, 100 and 200 mg/kg) showed significant inhibitory effect on growth of transplanted tumor in mice. At last, twenty-three C-3 monosaccharide oleanane-type triterpene saponins were tentatively identified, which may contributed to the anti-cancer activity of TSS. CONCLUSION This study demonstrated that TSS exhibited anti-proliferative and pro-apoptosis activities on MCF-7 cells via ROS-mediated activation of mitochondrial apoptosis pathway. TSS might be used as chemotherapeutic agent for the treatment of breast cancer with relatively low toxicity.
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Affiliation(s)
- Dandan Zhang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China
| | - Qiao Zhang
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Research Center for Clinical Pharmacy, First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, 310003, PR China
| | - Yunliang Zheng
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Research Center for Clinical Pharmacy, First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, 310003, PR China
| | - Jincai Lu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110006, PR China; Liaoning Provincial Key Laboratory of TCM Resources Conservation and Development, Shenyang Pharmaceutical University, Shenyang 110006, PR China.
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Xin T, Lu C. SirT3 activates AMPK-related mitochondrial biogenesis and ameliorates sepsis-induced myocardial injury. Aging (Albany NY) 2020; 12:16224-16237. [PMID: 32721927 PMCID: PMC7485737 DOI: 10.18632/aging.103644] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
Sirtuin-3 (SirT3) and AMPK stimulate mitochondrial biogenesis, which increases mitochondrial turnover and cardiomyocyte regeneration. We studied the effects of SirT3, AMPK, and mitochondrial biogenesis on sepsis-induced myocardial injury. Our data showed that after treating cardiomyocytes with lipopolysaccharide, SirT3 and AMPK levels decreased, and this was followed by mitochondrial dysfunction and cardiomyocyte death. Overexpression of SirT3 activated the AMPK pathway and improved mitochondrial biogenesis, which is required to sustain mitochondrial redox balance, maintain mitochondrial respiration, and suppress mitochondrial apoptosis. Inhibition of mitochondrial biogenesis abolished SirT3/AMPK-induced cardioprotection by causing mitochondrial damage. These findings indicate that SirT3 reduces sepsis-induced myocardial injury by activating AMPK-related mitochondrial biogenesis.
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Affiliation(s)
- Ting Xin
- Department of Cardiology, Tianjin First Central Hospital, Tianjing 300192, P.R. China
| | - Chengzhi Lu
- Department of Cardiology, Tianjin First Central Hospital, Tianjing 300192, P.R. China
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49
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Fu G, Wang B, He B, Feng M, Yu Y. LPS induces cardiomyocyte necroptosis through the Ripk3/Pgam5 signaling pathway. J Recept Signal Transduct Res 2020; 41:32-37. [PMID: 32580628 DOI: 10.1080/10799893.2020.1783682] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Necroptosis is a new type of cell death. However, the role of necroptosis in LPS-related cardiomyocyte damage has not been fully understood. The aim of our study is to explore the molecular mechanism underlying inflammation-mediated cardiomyocyte necroptosis. H9C2 cardiomyocyte cell line was treated with LPS. Then, cell viability and necroptosis were measured through qPCR and ELISA. Pathway analysis was performed to verify whether Ripk3/Pgam5 signaling pathway is implicated into the regulation of cardiomyocyte necroptosis. The results demonstrated that LPS reduced cardiomyocyte viability and activated necroptosis. At the molecular levels, oxidative stress and inflammation were triggered by LPS and these alterations may contribute to the activation of necroptosis. Finally, we found that Ripk3/Pgam5 signaling pathway was activated by LPS in cardiomyocyte and this signaling pathway may explain the regulatory mechanism underlying LPS-mediated necroptosis. Altogether, our results demonstrated that septic cardiomyopathy is associated with an activation of necroptosis through the Ripk3/Pgam5 signaling pathway.
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Affiliation(s)
- Guohua Fu
- Arrhythmia Center, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Binhao Wang
- Arrhythmia Center, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Bin He
- Arrhythmia Center, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Mingjun Feng
- Arrhythmia Center, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Yibo Yu
- Arrhythmia Center, Ningbo First Hospital, Ningbo, Zhejiang, China
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50
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Luo Y, Fan C, Yang M, Dong M, Bucala R, Pei Z, Zhang Y, Ren J. CD74 knockout protects against LPS-induced myocardial contractile dysfunction through AMPK-Skp2-SUV39H1-mediated demethylation of BCLB. Br J Pharmacol 2020; 177:1881-1897. [PMID: 31877229 PMCID: PMC7070165 DOI: 10.1111/bph.14959] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 11/18/2019] [Accepted: 12/06/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Lipopolysaccharides (LPS), an outer membrane component of Gram-negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF-CD74 in septic cardiomyopathy. EXPERIMENTAL APPROACH This study evaluated the impact of CD74 ablation on endotoxaemia-induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were examined. KEY RESULTS Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca2+ mishandling) and ultrastructural derangement associated with inflammation, O2 - production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down-regulated Skp2, an F-box component of Skp1/Cullin/F-box protein-type ubiquitin ligase, while up-regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP-LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS-induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5-AzaC ameliorated LPS-induced GFP-LC3B formation and cardiomyocyte contractile dysfunction. CONCLUSION AND IMPLICATIONS Our data suggested that CD74 ablation protected against LPS-induced cardiac anomalies, O2 - production, inflammation and apoptosis through suppression of autophagy in a Skp2-SUV39H1-mediated mechanism.
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Affiliation(s)
- Yuanfei Luo
- The Second Department of CardiologyThe Third Hospital of NanchangNanchangChina
- Jiangxi University of Traditional MedicineNanchangChina
| | - Congcong Fan
- The Second Department of CardiologyThe Third Hospital of NanchangNanchangChina
- Jiangxi University of Traditional MedicineNanchangChina
| | - Mingjie Yang
- Department of Cardiology and Shanghai Institute of Cardiovascular DiseasesFudan University Zhongshan HospitalShanghaiChina
| | - Maolong Dong
- Department of Burns, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Richard Bucala
- Department of MedicineYale School of MedicineNew HavenConnecticut
| | - Zhaohui Pei
- The Second Department of CardiologyThe Third Hospital of NanchangNanchangChina
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular DiseasesFudan University Zhongshan HospitalShanghaiChina
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular DiseasesFudan University Zhongshan HospitalShanghaiChina
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