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He J, Huang K, Fan X, Chang G. Sulfur Dioxide Alleviates Aortic Dissection Through Inhibiting Vascular Smooth Muscle Cell Phenotype Switch, Migration, and Proliferation via miR-184-3p/Cyp26b1 Axis. Antioxid Redox Signal 2025; 42:672-686. [PMID: 39834177 DOI: 10.1089/ars.2023.0471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Aims: Abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) are considered early events in the onset of thoracic aortic dissection (TAD). Endogenous sulfur dioxide (SO2), primarily produced by aspartate aminotransferase (AAT1) in mammals, has been reported to inhibit the migration and proliferation of VSMCs. However, the role of SO2 in the development of TAD remains unclear. Results: Endogenous SO2 production was decreased in aortic samples from patients with TAD. Supplementation with SO2 ameliorated β-aminopropionitrile-induced vascular injury in mice. Increasing the expression of SO2 pathway might reverse the abnormal migration, proliferation, and phenotypic switching in VSMCs. MicroRNA sequencing revealed miR-184-3p as the miRNA with the most significant increased expression level after AAT1 knockdown, and Cyp26b1 was predicted to be its potential target. A decrease in the SO2 pathway resulted in reduced Cyp26b1 expression, impairing VSMCs function, while restoring Cyp26b1 expression with miR-184-3p inhibitors could improve the VSMCs function. Innovation: This research extends the application of endogenous SO2 to the aortic diseases and elucidates the role of miRNA in endogenous SO2 regulatory network, highlighting its potential as a target for clinical practice. Conclusion: Endogenous SO2 inhibits the migration and proliferation of VSMCs in TAD progression via the miR-184-3p/Cyp26b1 axis. Antioxid. Redox Signal. 42, 672-686.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/pathology
- Animals
- Sulfur Dioxide/pharmacology
- Sulfur Dioxide/metabolism
- Mice
- Humans
- Aortic Dissection/metabolism
- Aortic Dissection/pathology
- Aortic Dissection/drug therapy
- Aortic Dissection/genetics
- Phenotype
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Male
- Cytochrome P-450 Enzyme System/metabolism
- Cytochrome P-450 Enzyme System/genetics
- Signal Transduction
- Oxygenases
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Affiliation(s)
- Jie He
- Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC Key Laboratory of Assisted Circulation (Sun Yat-Sen University), The First Affiliated Hospital, Sun Yat Sen University, Guangzhou, China
- Department of Cardiovascular Surgery, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kan Huang
- Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC Key Laboratory of Assisted Circulation (Sun Yat-Sen University), The First Affiliated Hospital, Sun Yat Sen University, Guangzhou, China
| | - Xiaoping Fan
- Department of Cardiovascular Surgery, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangqi Chang
- Division of Vascular Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC Key Laboratory of Assisted Circulation (Sun Yat-Sen University), The First Affiliated Hospital, Sun Yat Sen University, Guangzhou, China
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Liu HH, Wei W, Wu FF, Cao L, Yang BJ, Fu JN, Li JX, Liang XY, Dong HY, Heng YY, Zhang PF. Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway. BMC Cardiovasc Disord 2024; 24:354. [PMID: 38992615 PMCID: PMC11241843 DOI: 10.1186/s12872-024-03990-0] [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: 01/22/2024] [Accepted: 06/19/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.
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Affiliation(s)
- Hai-Hua Liu
- Department of Endocrinology, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yan'an South Road, Changzhi, 046000, Shanxi, China
| | - Wei Wei
- Department of Endocrinology, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yan'an South Road, Changzhi, 046000, Shanxi, China.
- Department of Pharmacology, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, 046000, Shanxi, China.
- Department of Clinical Center Laboratory, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yan'an South Road, Changzhi, 046000, Shanxi, China.
| | - Fei-Fei Wu
- Department of Endocrinology, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yan'an South Road, Changzhi, 046000, Shanxi, China
| | - Lu Cao
- Department of Endocrinology, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yan'an South Road, Changzhi, 046000, Shanxi, China
| | - Bing-Jie Yang
- Department of Stomatology, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, 046000, Shanxi, China
| | - Jia-Ning Fu
- Department of Stomatology, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, 046000, Shanxi, China
| | - Jing-Xia Li
- Department of Anesthesia, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, 046000, Shanxi, China
| | - Xin-Yue Liang
- Department of Medical Imageology, Changzhi Medical College, No.161, Jiefang East Street, Changzhi, 046000, Shanxi, China
| | - Hao-Yu Dong
- Department of Endocrinology, Heping Hospital Affiliated to Changzhi Medical College, No.110, Yan'an South Road, Changzhi, 046000, Shanxi, China
| | - Yan-Yan Heng
- Department of Nephrology Heping Hospital, Changzhi Medical College, No.110, Yanan Road South, Changzhi, 046000, Shanxi, China
| | - Peng-Fei Zhang
- Department of Nephrology Heping Hospital, Changzhi Medical College, No.110, Yanan Road South, Changzhi, 046000, Shanxi, China
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Li H, Gong J, Bian F, Yu F, Yuan H, Hu F. The role and mechanism of NLRP3 in wasp venom-induced acute kidney injury. Toxicon 2024; 238:107570. [PMID: 38103798 DOI: 10.1016/j.toxicon.2023.107570] [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: 10/08/2023] [Revised: 12/04/2023] [Accepted: 12/14/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND Inflammation and pyroptosis have crucial impacts on the development of acute kidney injury (AKI) and have been validated in a variety of existing AKI animal models. However, the mechanisms underlying wasp venom-induced AKI are still unclear. The involvement of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) in some mouse models of AKI has been extensively documented, and its crucial function in controlling inflammation and pyroptosis has been highlighted. The objective of our study was to investigate the role and mechanism of NLRP3 in inflammation and pyroptosis associated with wasp venom-induced AKI. METHODS A mouse model of AKI induced by wasp venom pre-injected with an NLRP3 inhibitor was used to study the role and mechanism of NLRP3. To verify the importance of NLRP3, western blotting was performed to assess the expression of NLRP3, caspase-1 p20, and gasdermin D (GSDMD)-N. Additionally, quantitative real-time polymerase was used to determine the expression of NLRP3, caspase-1, and GSDMD. Furthermore, enzyme-linked immunosorbent assay was utilized to measure the levels of interleukin (IL)-1β and IL-18. RESULTS NLRP3 was found to be the downstream signal of the stimulator of interferon genes in the wasp sting venom-induced AKI model. The administration of wasp venom in mice significantly upregulated the expression of NLRP3, leading to renal dysfunction, inflammation, and pyroptosis. Treatment with an NLRP3 inhibitor reversed the renal damage induced by wasp venom and attenuated pathological injury, inflammatory response, and pyroptosis. CONCLUSION NLRP3 activation is associated with renal failure, inflammatory response and pyroptosis in the hyper early phase of wasp venom-induced AKI. The inhibition of NLRP3 significantly weakened this phenomenon. These findings could potentially offer a viable therapeutic approach for AKI triggered by wasp venom.
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Affiliation(s)
- Haoran Li
- School of Medicine, Wuhan University of Science and Technology, Wuhan, China; Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Jianhua Gong
- Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Fang Bian
- Department of Pharmacy, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Fanglin Yu
- School of Medicine, Wuhan University of Science and Technology, Wuhan, China; Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Hai Yuan
- Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
| | - Fengqi Hu
- Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
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You D, Nie K, Wu X, Weng M, Yang L, Chen Y, Cui J, Wan J. C3a/C3aR synergies with TGF-β to promote epithelial-mesenchymal transition of renal tubular epithelial cells via the activation of the NLRP3 inflammasome. J Transl Med 2023; 21:904. [PMID: 38082306 PMCID: PMC10714586 DOI: 10.1186/s12967-023-04764-6] [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: 09/23/2023] [Accepted: 11/25/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Complement component 3a and its receptor (C3a/C3aR) and the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome contribute to epithelial-mesenchymal transition (EMT). However, the relationship between C3a/C3aR and the NLRP3 inflammasome in EMT remains unclear. This study aimed to elucidate the roles of C3a/C3aR and the NLRP3 inflammasome involved in TGF-β-induced EMT. METHOD Mouse renal tubular epithelial cells (TCMK-1) were exposed to C3a and TGF-β for 48 h. C3aR antagonist, MCC950, an inhibitor of the NLRP3 inflammasome and PD98059, an inhibitor of ERK signaling, were respectively applied to pretreat the cells at 30 min before C3a and TGF-β administration.The cells were collected for western blot, immunofluorescence staining and ELISA. Unilateral ureteral obstruction (UUO) models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950 was intraperitoneally injected in UUO mice. Kidney samples were collected for immunohistochemistry staining. RESULTS In vitro, C3a synergized with TGF-β to promote EMT and the activation of the NLRP3 inflammasome. Inhibition of C3aR attenuated EMT and the activation of the NLRP3 inflammasome. Inhibition of the NLRP3 inflammasome alleviated EMT but didn't affect the expression of C3aR. Inhibition of ERK signaling inhibited the activation of the NLRP3 inflammasome. In vivo, the expression of IL-1β was significantly higher in UUO mice compared to the sham-operated mice. C3aR deficiency and inhibition of the NLRP3 Inflammasome contributed to decreased IL-1β in UUO mice. CONCLUSION Our data revealed that C3a/C3aR synergies with TGF-β to activate the NLRP3 inflammasome to promote epithelial-mesenchymal transition of renal tubular epithelial cells through ERK signaling, and the way in which C3aR activates the inflammasome is to promote the assembly of the NLRP3 inflammasome.
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Affiliation(s)
- Danyu You
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Kun Nie
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xiaoting Wu
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Mengjie Weng
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Liyan Yang
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yi Chen
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jiong Cui
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jianxin Wan
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China.
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
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Zhu J, Wang Y, Rivett A, Li H, Wu L, Wang R, Yang G. Deficiency of cystathionine gamma-lyase promotes aortic elastolysis and medial degeneration in aged mice. J Mol Cell Cardiol 2022; 171:30-44. [PMID: 35843061 DOI: 10.1016/j.yjmcc.2022.06.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 11/28/2022]
Abstract
Enzymatic degradation of elastin by matrix metalloproteinases (MMPs) leads to the permanent dilation of aortic wall and constitutes the most prominent characters of aortic aneurysm and aging-related medial degeneration. Hydrogen sulfide (H2S) as a gasotransmitter exhibits a wide variety of cardio-protective functions through its anti-inflammatory and anti-oxidative actions. Cystathionine gamma-lyase (CSE) is a main H2S-generating enzyme in cardiovascular system. The regulatory roles of CSE/H2S system on elastin homeostasis and blood vessel degeneration have not yet been explored. Here we found that aged CSE knockout mice had severe aortic dilation and elastic degradation in abdominal aorta and were more sensitive to angiotensin II-induced aortic elastolysis and medial degeneration. Administration of NaHS would protect the mice from angiotensin II-induced inflammation, gelatinolytic activity, elastin fragmentation, and aortic dilation. In addition, human aortic aneurysm samples had higher inflammatory infiltration and lower expression of CSE. In cultured smooth muscle cells (SMCs), TNFα-induced MMP2/9 hyperactivity and elastolysis could be attenuated by exogenously applied NaHS or CSE overexpression while further deteriorated by complete knockout of CSE. It was further found that H2S inhibited MMP2 transcription by posttranslational modification of Sp1 via S-sulfhydration. H2S also directly suppressed MMP hyperactivity by S-sulfhydrating the cysteine switch motif. Taken together, this study revealed the involvement of CSE/H2S system in the pathogenesis of aortic elastolysis and medial degeneration by maintaining the inactive form of MMPs, suggesting that CSE/H2S system can be a target for the prevention of age-related medial degeneration and treatment of aortic aneurysm.
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Affiliation(s)
- Jiechun Zhu
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Yuehong Wang
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Alexis Rivett
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Hongzhu Li
- School of Medicine, Xiamen University, Xiamen, China; Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Lingyun Wu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; Department of Biology, York University, Toronto, Canada
| | - Rui Wang
- Department of Biology, York University, Toronto, Canada
| | - Guangdong Yang
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
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Wang Y, Gao P, Li F, Du J. Insights on aortic aneurysm and dissection: Role of the extracellular environment in vascular homeostasis. J Mol Cell Cardiol 2022; 171:90-101. [DOI: 10.1016/j.yjmcc.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/06/2022] [Accepted: 06/29/2022] [Indexed: 11/29/2022]
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Gupta R, Sahu M, Tripathi R, Ambasta RK, Kumar P. Protein S-sulfhydration: Unraveling the prospective of hydrogen sulfide in the brain, vasculature and neurological manifestations. Ageing Res Rev 2022; 76:101579. [PMID: 35124235 DOI: 10.1016/j.arr.2022.101579] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/30/2022] [Accepted: 02/01/2022] [Indexed: 02/08/2023]
Abstract
Hydrogen sulfide (H2S) and hydrogen polysulfides (H2Sn) are essential regulatory signaling molecules generated by the entire body, including the central nervous system. Researchers have focused on the classical H2S signaling from the past several decades, whereas the last decade has shown the emergence of H2S-induced protein S-sulfhydration signaling as a potential therapeutic approach. Cysteine S-persulfidation is a critical paradigm of post-translational modification in the process of H2S signaling. Additionally, studies have shown the cross-relationship between S-sulfhydration and other cysteine-induced post-translational modifications, namely nitrosylation and carbonylation. In the central nervous system, S-sulfhydration is involved in the cytoprotection through various signaling pathways, viz. inflammatory response, oxidative stress, endoplasmic reticulum stress, atherosclerosis, thrombosis, and angiogenesis. Further, studies have demonstrated H2S-induced S-sulfhydration in regulating different biological processes, such as mitochondrial integrity, calcium homeostasis, blood-brain permeability, cerebral blood flow, and long-term potentiation. Thus, protein S-sulfhydration becomes a crucial regulatory molecule in cerebrovascular and neurodegenerative diseases. Herein, we first described the generation of intracellular H2S followed by the application of H2S in the regulation of cerebral blood flow and blood-brain permeability. Further, we described the involvement of S-sulfhydration in different biological and cellular functions, such as inflammatory response, mitochondrial integrity, calcium imbalance, and oxidative stress. Moreover, we highlighted the importance of S-sulfhydration in cerebrovascular and neurodegenerative diseases.
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NLRP3 Inflammasome in Vascular Disease: A Recurrent Villain to Combat Pharmacologically. Antioxidants (Basel) 2022; 11:antiox11020269. [PMID: 35204152 PMCID: PMC8868353 DOI: 10.3390/antiox11020269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 02/07/2023] Open
Abstract
Despite the great advances in medicine, mortality from cardiovascular diseases keeps on growing. This tendency is not likely to change considering the pandemic proportions of obesity and diabetes. Besides, the global population is more aged as life expectancy increases, and vascular aging plays a key role in the increased risk of vascular disease. In light of recent trials, namely the CANTOS study, showing the enormous potential of anti-inflammatory therapies and in particular those targeted to IL-1β, a change in therapeutical management of cardiovascular diseases is coming about. The NLRP3 inflammasome is a multiprotein complex that assembles to engage the innate immune defense by processing the maturation of pro-inflammatory cytokines IL-1β and IL-18. Substantial evidence has positioned the NLRP3 inflammasome at the center of vascular disease progression, with a particular significance in the context of aging and the low-grade chronic inflammation associated (inflammaging). Therefore, pharmacological blockade of the NLRP3 inflammasome and its end products has arisen as an extremely promising tool to battle vascular disease. In this review, we discuss the mechanisms by which the NLRP3 inflammasome contributes to vascular disease, with particular attention to the consequences of aging, and we enumerate the therapeutic options available to combat this recurrent villain.
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Wortmann M, Klotz R, Kalkum E, Dihlmann S, Böckler D, Peters AS. Inflammasome Targeted Therapy as Novel Treatment Option for Aortic Aneurysms and Dissections: A Systematic Review of the Preclinical Evidence. Front Cardiovasc Med 2022; 8:805150. [PMID: 35127865 PMCID: PMC8811141 DOI: 10.3389/fcvm.2021.805150] [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: 10/29/2021] [Accepted: 12/28/2021] [Indexed: 12/09/2022] Open
Abstract
Both aortic aneurysm and dissection are life threatening pathologies. In the lack of a conservative medical treatment, the only therapy consists of modifying cardiovascular risk factors and either surgical or endovascular treatment. Like many other cardiovascular diseases, in particular atherosclerosis, aortic aneurysm and dissection have a strong inflammatory phenotype. Inflammasomes are part of the innate immune system. Upon stimulation they form multi protein complexes resulting mainly in activation of interleukin-1β and other cytokines. Considering the gathering evidence, that inflammasomes are decisively involved in the emergence and progression of aortic diseases, inflammasome targeted therapy provides a promising new treatment approach. A systematic review following the PRISMA guidelines on the current preclinical data regarding the potential role of inflammasome targeted drug therapy as novel treatment option for aortic aneurysms and dissections was performed. Included were all rodent models of aortic disease (aortic aneurysm and dissection) evaluating a drug therapy with direct or indirect inhibition of inflammasomes and a suitable control group with the use of the same aortic model without the inflammasome targeted therapy. Primary and secondary outcomes were incidence of aortic disease, aortic rupture, aortic related death, and the maximum aortic diameter. The literature search of MEDLINE (via PubMed), the Web of Science, EMBASE and the Cochrane Central Registry of Registered Trials (CENTRAL) resulted in 8,137 hits. Of these, four studies met the inclusion criteria and were therefore eligible for data analysis. In all of them, targeting of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome effectively reduced the incidence of aortic disease and aortic rupture, and additionally reduced destruction of the aortic wall. Treatment strategies aiming at other inflammasomes could not be identified. In conclusion, inflammasome targeted therapies, more precisely targeting the NLRP3 inflammasome, have shown promising results in rodent models and deserve further investigation in preclinical research to potentially translate them into clinical research for the treatment of human patients with aortic disease. Regarding other inflammasomes, more preclinical research is needed to investigate their role in the pathophysiology of aortic disease. Protocol Registration: PROSPERO 2021 CRD42021279893, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021279893
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Affiliation(s)
- Markus Wortmann
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
- *Correspondence: Markus Wortmann
| | - Rosa Klotz
- Study Center of the German Surgical Society (SDGC), University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Eva Kalkum
- Study Center of the German Surgical Society (SDGC), University of Heidelberg, Heidelberg, Germany
| | - Susanne Dihlmann
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Dittmar Böckler
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Andreas S. Peters
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
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