Papillary thyroid cancer (PTC) is a general thyroid cancer subtype; however, PTC is associated with metastasis or recurrence via anti-cancer drug resistance, rendering it practically incurable. Therefore, effective and reliable clinical approaches are urgently required.

We demonstrated the coordinated up-regulation of sarco/endoplasmic reticulum (ER) calcium ATPase 1 (SERCA1) in metastatic PTC under treatment with sorafenib or lenvatinib. We screened novel drug candidates in a patient-derived lymph node metastatic PTC and compared outcomes with those in non-metastatic and main mass PTC in an in vitro and in vivo model to propose a new clinical strategy.

In the current study using patient-derived metastatic PTC cells, SERCA1 was considerably increased under sorafenib- or lenvatinib-treated conditions. SERCA is a critical component in cytosolic free calcium regulation and is regulated by calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) via NFκB. However, cardiac dysfunction was inevitable in vivo because of non-specific inhibition of SERCA isoforms by conventional SERCA inhibitors. This study designed a therapeutic approach with decreased cardiac dysfunction via SERCA1 isoform-specific inhibition by novel small molecules, CKP1 and CKP2, under severe ER stress conditions in patient-derived metastatic PTC. These novel SERCA1-specific inhibitors remarkably increased tumour shrinkage in the patient-derived metastatic PTC xenograft tumour model without cardiac dysfunction when used in combination with sorafenib or lenvatinib.

These outcomes suggest the potential efficacy of the novel combination strategy that uses targeted therapy to treat malignant cancer cells, such as sorafenib- or lenvatinib-resistant cancer cells.

Cardiovascular disease is the predominant cause of mortality and severe disability. Cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs) have good application prospects for treating this disease. Unfortunately, CMs generated via current methods are relatively immature, as proven by defects such as sarcomer-like structures, calcium processing capacity and mitochondrial maturity. Therefore, in this study, tunable PDMS substrates that modified with sufficiently thick synthetic coatings were prepared to regulate both the myocardial differentiation of hESCs and subsequent maturation. Surprisingly, the effect of substrate elasticity on the critical attachment of hESCs and hESC-CMs vanished when common Matrigel coatings were used, but apparent differences were detected in the synthetic group. Rigid substrates promoted the adhesion of hESCs but not hESC-CMs. Moreover, the PDMS substrates with the highest hardness remarkably promoted the myocardial differentiation of hESCs, which was even better than that of the rigid plate group. The softest PDMS achieved the best performance among the groups in terms of the maturation of hESC-CMs, as confirmed by enhanced functional, metabolic, and ultrastructural maturation. This study reveals the real impact of an elastic substrate on the adhesion, differentiation, and maturation of hESC-CMs, which has value for accelerating the development of clinically applicable mature hESC-CMs with high induction efficiency.

Pre-clinical evidence indicates that mitochondria may be a therapeutic target for luteolin (3',4',5,7-tetrahydroxyflavone; LUT) in different conditions. LUT modulates mitochondrial physiology in in vitro, ex vivo, and in vivo experimental models. This flavone exerted mitochondria-related antioxidant and anti-apoptotic effects, stimulated mitochondrial fusion and fission, induced mitophagy, and promoted mitochondrial biogenesis in human and animal cells and tissues. Moreover, LUT modulated the activity of components of the oxidative phosphorylation (OXPHOS) system, improving the ability of mitochondria to produce adenosine triphosphate (ATP) in certain circumstances. The mechanism of action by which LUT promoted mitochondrial benefits and protection are not completely clear yet. Nonetheless, LUT is a potential candidate to be utilized in mitochondrial therapy in the future. In this work, it is explored the mechanisms of action by which LUT modulates mitochondrial physiology in different pre-clinical experimental models.

Sarco/endoplasmic reticulum (SR/ER) Ca2+-ATPase (SERCA) pumps are ubiquitous membrane proteins in all eukaryotic cells, playing a central role in maintaining intracellular calcium homeostasis by re-sequestering Ca2+ ions from the cytosol into the SR/ER at the expense of ATP hydrolysis. SERCA pumps are well-characterized components of the calcium transport machinery in the cell, playing a role in various physiological processes, including muscle contraction, energy metabolism, secretion exocytosis, gene expression, synaptic transmission, cell survival, and fertilization. Allosteric regulation of SERCA pumps plays a key role in health and disease, and modulation of the SERCA pumps has emerged as a therapeutic approach for the treatment of cardiovascular, muscular, metabolic, and neurodegenerative disorders. In this review, we provide a comprehensive overview of the structural dynamics underlying allosteric modulation of SERCA, focusing on the effects of endogenous regulatory proteins, Ca2+ ions, ATP, and small-molecule effectors on the dynamics and function of the pump. We also examine in detail the role of posttranslational modifications as allosteric modulators of SERCA function, focusing on the oxidative modifications S-glutathionylation, S-nitrosylation, tyrosine nitration, and carbonylation, and non-oxidative modifications that include SUMOylation, acetylation, O-GlcNAcylation, phosphorylation, and ubiquitination. Finally, we discuss the therapeutic potential and challenges of allosteric modulation of SERCA pumps, including the design of small-molecule effectors, microRNA-based interventions, and targeted strategies that modulate SERCA posttranslational regulation. Overall, this review aims to bridge the gap between the mechanisms underlying allosteric modulation of SERCA and the translation of basic science discoveries into effective therapies targeting SERCA pumps.

Malignant arrhythmia induced by traumatic hemorrhage is a leading cause of early mortality in hemorrhagic shock. Understanding the mechanisms driving these arrhythmias and identifying therapeutic targets are critical for improving early survival in patients with traumatic hemorrhagic shock.

Peripheral blood samples from patients with hemorrhagic shock were collected and analyzed for peptidylarginine deiminase 2 (PAD2) protein levels using ELISA. Pad2 knockout mice (Pad2-/-, Pad2 KO) were generated, and the hemorrhagic shock model was constructed via femoral artery cannulation and bloodletting. Cardiomyocytes were isolated and contractility and calcium content were measured by confocal microscopy. PAD2 subcellular localization was assessed through immunofluorescence and Western blotting. Proteins interacting with PAD2 in cardiomyocytes were identified using co-immunoprecipitation followed by mass spectrometry (CoIP-MS). The effect of PAD2 on sarcoplasmic reticulum calcium-ATPase 2a (SERCA2a) activity and citrullination was evaluated through enzyme activity assays and protein citrullination detection. AAV9-PAD2 was injected into mice via tail vein to induce in vivo overexpression of PAD2 in the myocardium. The effects of PAD2 enzymatic activity mutations and a PAD2-specific inhibitor on survival rate and arrhythmia following hemorrhagic shock were assessed through intraperitoneal injection.

PAD2 protein levels were significantly elevated in the peripheral blood of patients with hemorrhagic shock. Pad2 knockout improved calcium homeostasis in the sarcoplasmic reticulum of cardiomyocytes and alleviated post-shock arrhythmia in mice. Following hypoxia, PAD2 exhibited increased colocalization with the sarcoplasmic reticulum. During hypoxia, PAD2 inhibited SERCA2a activity through citrullination. AAV9-mediated overexpression of PAD2 in cardiomyocytes worsened both survival rates and the incidence of ventricular arrhythmia following hemorrhagic shock in mice. Conversely, PAD2 enzymatic activity mutations and a PAD2-specific inhibitor improved survival rates and reduced arrhythmia after hemorrhagic shock.

During myocardial hypoxia occurs in hemorrhagic shock, PAD2 reduces SERCA2a enzyme activity by citrullination, disrupting myocardial calcium homeostasis. Peptidylarginine deiminase 2 gene deficiency or inhibition improves ventricular arrhythmias and increases survival following hemorrhagic shock.

Original Research-basic sciences research; not applicable.

Cardiovascular diseases (CVDs) have become the leading cause of death globally, surpassing infectious diseases and other chronic illnesses. The incidence and mortality rates of CVDs are rising worldwide, posing a key challenge in public health. The ubiquitination system is a vast and complex. It is an important post-translational modification that plays a crucial role in various cellular processes. Deubiquitination is catalyzed by deubiquitinases (DUBs), which remove ubiquitin (Ub) from ubiquitinated proteins, thereby reversing the ubiquitination process. DUBs play an important role in many biological processes, such as DNA repair, cell metabolism, differentiation, epigenetic regulation, and protein stability control. They also participate in the regulation of many signaling pathways associated with the development and progression of CVDs. In this review, we primarily focus on the role of DUBs in various key pathological mechanisms of atherosclerosis (AS), such as foam cell formation, vascular remodeling (VR), endothelial-to-mesenchymal transition (End-MT), and clonal hematopoiesis (CH). In the heart, we summarize the involvement of DUBs in diseases and pathological processes, including heart failure (HF), myocardial infarction (MI), myocardial hypertrophy (MH) and ischemia/reperfusion (I/R) injury. Additionally, we also explore the diabetic cardiomyopathy (DCM) and the use of doxorubicin-induced cardiotoxicity in clinical settings. A comprehensive understanding of deubiquitination may provide new insights for the treatment and drug design of CVDs.

With rising incidence, mortality and limited therapeutic options, heart failure with preserved ejection fraction (HFpEF) remains one of the most important topics in cardiovascular medicine today. Characterised by left ventricular diastolic dysfunction partially due to impaired Ca2+ homeostasis, one ion channel in particular, SarcoEndoplasmic Reticulum Ca2+-ATPase (SERCA2a), may play a significant role in its pathophysiology. A better understanding of the complex mechanisms interplaying to contribute to SERCA2a dysfunction will help develop treatments targeting it and thus address the growing clinical challenge HFpEF poses. This review examines the conflicting evidence present for changes in SERCA2a expression and activity in HFpEF, explores potential underlying mechanisms, and finally evaluates the drug and gene therapy trials targeting SERCA2a in heart failure. Recent positive results from trials involving widely used anti-diabetic agents such as sodium-glucose co-transporter protein 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) agonists offer advancement in HFpEF management. The potential interplay between these agents and SERCA2a regulation presents a novel angle that could open new avenues for modulating diastolic function; however, the mechanistic research in this emerging field is limited. Overall, the direct role of SERCA2a dysfunction in HFpEF remains undetermined, highlighting the need for well-designed pre-clinical studies and robust clinical trials.

The oviduct is an organ that participates in multiple critical reproductive processes and provides essential nutritional support while maintaining a specialized microenvironment. It is particularly vulnerable to damage following heat stress-induced hyperthermia. Therefore, mitigating heat-induced damage to oviduct epithelial cells while preserving their physiological integrity under hyperthermia represents a critical therapeutic goal.

This study aims to simulate the cellular damage state in yak oviduct epithelial cells (YOECs) under thermal challenge by increasing the incubation temperature of cultured cells, while observing changes in cellular injury upon supplementation with 17β-estradiol (E2), in order to explore the underlying cellular regulatory mechanisms involved.

After 48 h of exposure to 41 °C, YOECs exhibited elevated HSP70 and HSP90 protein expression levels, reduced OVGP1 protein expression, and increased apoptotic cells. Compared to the 41 °C group, the E2 + 41 °C group displayed decreased HSP70 protein levels, increased OVGP1 protein expression, and reduced apoptotic cell numbers. Additionally, changes in endoplasmic reticulum calcium ion (ER-Ca2+) distribution and fluorescence intensity variations in ER-Ca2+ regulatory proteins SERCA and IP3R3 were analyzed in the 37 °C, 41 °C, and E2 + 41 °C groups. The ER-Ca2+ distribution pattern in the E2 + 41 °C group remained similar to that of the 37 °C group. However, the fluorescence intensity levels of SERCA and IP3R3 proteins in the E2 + 41 °C group did not recover to levels comparable to the 37 °C group.

These findings suggest that E2 may mitigate thermal challenge-induced cellular damage in YOECs by maintaining ER-Ca2+ homeostasis, thereby preserving cellular functionality under elevated temperatures.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder. Despite the availability of numerous pharmacotherapies, a range of adverse reactions, including hypoglycemia, gastrointestinal discomfort, and lactic acidosis, limits their patient applicability and long-term application. Therefore, it is necessary to screen novel therapeutic drugs for T2DM treatment that have high efficacy but few adverse effects. AMP-activated protein kinase (AMPK) stands out as one of the most powerful targets for T2DM treatment. It can be activated through energy-sensing or calcium signaling. Medications that activate AMPK through the energy-sensing mechanism exhibit remarkable potency, but they are accompanied by lactic acidosis, carrying an alarmingly high mortality rate. Interestingly, medications that activate AMPK through calcium signaling, such as gliclazide, seldom induce lactic acidosis. However, the efficacy of gliclazide is much lower than metformin. Therefore, it is necessary to explore targets that activate AMPK via calcium signaling to avoid lactic acidosis while maintaining high potency. Ion channels are the main controller of intracellular calcium flow. Specific agonists and inhibitors targeting ion channels have been reported to activate AMPK. In this review, we will summarize the structure and function of calcium-permeable ion channels and discuss the potential of targeting these calcium channels for T2DM treatment.

Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas-including LMCs-of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.

Gnathodiaphyseal dysplasia (GDD) is a rare genetic syndrome characterized by cemento-ossifying fibroma lesions in the mandible and sclerosis of tubular bones. Currently, the clinical treatment of GDD is limited to surgical resection; therefore, novel treatment strategies developed through exploration of the related mechanisms are needed. Mutations in the TMEM16E/ANO5 gene are considered the main pathogenic factor of GDD, and the Ano5 knockout mouse model (Ano5-/-) established previously, which presented GDD-like characteristics, exhibited decreased osteoclastogenesis. ANO5, a calcium-activated chloride channel (CaCC), plays an important role in the maintenance of intracellular calcium homeostasis, which is crucial for osteoclast differentiation. In this study, our data indicated that the intracellular calcium concentration ([Ca2+]i) and calcium transients were significantly decreased in Ano5-/- osteoclasts accompanied by abnormally altered expression of calcium transporters, resulting in calcium dyshomeostasis. In addition, the endoplasmic reticulum stress (ERS) response was significantly enhanced in Ano5-/- osteoclasts, possibly because of calcium dyshomeostasis, which leading to the increased proportion of apoptotic osteoclasts via the activation of the C/EBP homologous protein (CHOP) signalling pathway, accompanied by abnormal changes in the expression of apoptosis-related factors. In summary, Ano5 deficiency impairs the function of osteoclasts by increasing osteoclast apoptosis, which is induced by an overactivated ERS response via calcium dyshomeostasis.

Intracellular Ca2+ cycling governs effective myocardial systolic contraction and diastolic relaxation. SERCA2a (sarco/endoplasmic reticulum Ca2+ ATPase type 2a), which plays a crucial role in controlling intracellular Ca2+ signaling and myocardial cell function, is downregulated and inactivated during sepsis-induced heart dysfunction. However, the cause of this dysregulation remains unclear. In this study, we investigated the effect of lysine succinylation in lipopolysaccharide-induced septic heart dysfunction through global succinylome analysis of myocardial tissues from septic rats.

We conducted a succinylome profiling and developed a protein language model-based framework to prioritize succinylation at a functionally important site, and further analysis revealed crosstalk between ubiquitination and succinylation of SERCA2a. The succinylation of SERCA2a in septic rats or lipopolysaccharide-treated cells were detected by co-immunoprecipitation. Thereafter, a desuccinylated SERCA2aK352R was introduced and its function and stability were determined by Ca2+ transient and Western blot, respectively. Meanwhile, the effect on SERCA2aK352R on heart function was assessed in vivo by echocardiography and hemodynamics.

We identified 10 324 succinylated lysine sites in heart tissues, including 1042 differentially succinylated lysine sites, in response to lipopolysaccharide. SERCA2a was hypersuccinylated in the myocardial tissues of septic rats and lipopolysaccharide-treated cardiomyocytes. Increased ubiquitination level, reduced protein level, and activity of SERCA2a were observed, along with increased succinylation of SERCA2a in vivo and in vitro. K352 was essential for SERCA2a succinylation, which reduced SERCA2a protein level by promoting formation of the K48 ubiquitin chain on SERCA2a and its degradation by proteasomes. Co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry identified that SIRT2 (sirtuin2), a deacylase, exhibited interaction with SERCA2a. Furthermore, SIRT2 decreased K352 succinylation of SERCA2a, suggesting that SIRT2 may function as a desuccinylase for SERCA2a.

Succinylation of SERCA2a at K352, which was controlled by SIRT2, promotes its ubiquitinoylation and degradation by proteasomes in sepsis-induced heart dysfunction.

Heart failure with reduced ejection fraction (HFrEF) remains a global health challenge, associated with high morbidity, mortality, and rising healthcare costs. Despite advances in guideline-directed therapy, many patients, especially those with severely reduced ejection fraction, remain symptomatic. Traditional inotropes, including β-agonists and phosphodiesterase inhibitors, are limited in chronic HFrEF due to risks of arrhythmias, calcium overload, and increased myocardial oxygen demand. Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that enhances systolic contraction by increasing the efficiency of actin-myosin interactions. It prolongs systolic ejection time and improves stroke volume without elevating intracellular calcium or energy consumption. Although theoretical concerns exist regarding impaired diastolic filling, clinical trials have not confirmed such adverse effects in most patients. This narrative review discusses OM's pharmacologic profile, clinical trial data, and its potential as an adjunct therapy in advanced HFrEF. While not yet guideline-recommended, OM may benefit patients who remain symptomatic despite optimal treatment.

Acute myocardial infarction (AMI) is a common cardiovascular disease with high morbidity and mortality rates. Allicin, the primary active component of traditional Chinese herbs garlic, has multiple cardiovascular effects. However, the protective effect of allicin on AMI is rare. This study aimed to identify the pathways through which allicin stimulates hydrogen sulfide (H2S) production to regulate calcium ion (Ca2+) homeostasis in cardiomyocytes, thereby contributing to AMI protection.

In this study, we established an AMI rat model by ligating the left anterior descending branch of the coronary artery to assess the therapeutic effect of allicin. We also investigated its influence on cardiomyocyte Ca2+ homeostasis. To determine the role of H2S production in the effects of allicin, we identified the H2S synthase in healthy rat myocardial tissue and serum and then applied H2S synthase inhibitors to block H2S production.

The results indicate that allicin significantly enhanced cardiac function, raised H2S levels in myocardial tissue and serum, reduced necrosis tissue size, decreased myocardial enzyme levels, and improved myocardial pathological changes. Surprisingly, allicin also notably increased H2S synthase levels. These findings suggest that allicin shields AMI rats by stimulating H2S production, acting both as a direct H2S donor and indirectly boosting H2S synthase expression. Furthermore, allicin enhanced Ca2+ homeostasis in cardiomyocytes by improving cardiomyocyte contraction kinetics and regulating the function and expression of key proteins related to Ca2+ transport in cardiomyocytes. The effect of allicin on Ca2+ homeostasis was partially decreased but not entirely abolished when H2S production was inhibited using H2S synthase inhibitors PAG and AOAA. This suggests that while the impact of allicin is strongly associated with H2S, additional independent mechanisms are also involved.

Our study presents novel evidence demonstrating that allicin modulates Ca2+ homeostasis in cardiomyocytes by stimulating H2S production, thereby conferring protection against AMI. Furthermore, the protective effects of allicin are partly mediated by, but not solely reliant on, the generation of H2S. These findings not only provide mechanistic insights into the anti-AMI effects of allicin but also underscore its therapeutic promise.

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.

The clinical use of the anticancer drug doxorubicin (DOX) is limited due to its time- and dose-dependent cardiotoxicity. Therefore, there is an urgent need to explore the molecular mechanism and coping strategies for alleviating DOX-induced cardiotoxicity (DIC) and solve the difficulties in clinical application. The role and mechanism of androgen receptor (AR), which is the target of androgen, in DIC remain unclear. Here, we elucidated the molecular mechanisms of AR in DOX-induced cardiotoxicity. Inhibition of AR aggravated the DOX-induced cardiac function impairment, while the activation of AR showed obvious therapeutic effect and rescued cardiac function of rats. AR can physically interact with SERCA2a. Activation of AR participates in the regulation of DOX-induced myocardial injury by modulating SERCA2a, attenuating DOX-induced endoplasmic reticulum stress, improving calcium (Ca2+) cycling homeostasis, and inhibiting ROS levels and apoptosis, thereby participating in the regulation of DOX induced myocardial injury. Altogether, these findings reveal for the first time the relationship and role between AR and SERCA2a in regulating the progression of DIC, suggesting that AR may play a therapeutic role as a new target against DIC.

Heart failure (HF) remains a major cause of mortality worldwide. While novel approaches, including gene and cell therapies, show promise, efficient delivery methods for such biologics to the heart are critically needed. One emerging strategy is lung-to-heart delivery using nanoparticle (NP)-encapsulated biologics. This study examines the efficiency of delivering a therapeutic peptide conjugated to a cell-penetrating peptide (CPP) to the heart via the lung-to-heart route through intratracheal (IT) injection in mice. The CPP, a tandem repeat of NP2 (dNP2) derived from the human novel LZAP-binding protein (NLBP), facilitates intracellular delivery of the therapeutic payload. The therapeutic peptide, SE, is a decoy peptide designed to inhibit protein phosphatase 1 (PP1)-mediated dephosphorylation of phospholamban (PLN). Our results demonstrated that IT injection of dNP2-SE facilitated efficient delivery to the heart, with peak accumulation at 3 h post-injection. The administration of dNP2-SE significantly ameliorated morphological and functional deterioration of the heart under myocardial infarction. At the molecular level, dNP2-SE effectively prevented PLN dephosphorylation in the heart. Immunoprecipitation experiments further revealed that dNP2-SE binds strongly to PP1 and disrupts its interaction with PLN. Collectively, our findings suggest that lung-to-heart delivery of a CPP-conjugated therapeutic peptide, dNP2-SE, represents a promising approach for the treatment of HF.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD). Although surgical correction of TOF is possible, patients often face challenges related to right ventricle dysfunction (RVD) post-surgery, which can significantly impact their long-term survival. The causes of RVD in TOF patients are complex, involving both the unique structural characteristics of the TOF heart and damage resulting from surgical interventions. Residual anatomical issues following TOF repair are often unavoidable, placing the RV under stress and leading to the activation of multiple molecular pathways. This review comprehensively outlines the causes of RVD in patients after TOF surgery, particularly focusing the molecular pathways that contribute to RVD, including established signaling pathways as well as emerging pathways identified through transcriptomic analysis of RV myocardium in TOF patients. We also highlight the features of these molecular pathways concerning RVD, as well as the influence of gender disparities on these molecular pathways. By interpreting the causes and molecular mechanisms underlying RVD after TOF surgery, this review provides new insights for managing RVD in repaired TOF, potentially paving the way for targeted therapies aimed at improving long-term outcomes for those affected by RVD.

Myocardial ischemia-reperfusion injury (MIRI) often leads to irreversible myocardium dysfunction, while existing therapies are palliatives that transiently alleviate the disease symptoms. Repairing sarcoplasmic reticulum Ca2+-ATPase (SERCA) could reverse MIRI, which, however, requires precise drug delivery to the sarcoplasmic reticulum (SR). To this end, we leverage cell-cell "NETwork" of neutrophils to deliver SERCA activator-loaded SR-localized nanoparticles (L-P-NPs) to the damaged myocardial cells, following a hierarchical targeting process: (i) chemotactic neutrophils deliver L-P-NPs to ischemia-reperfused heart, achieving tissue level targeting; (ii) neutrophils produce neutrophil extracellular traps (NETs) to transport L-P-NPs to injured myocardial cell, achieving cellular level targeting; (iii) L-P-NPs escort therapeutic payloads to the SR, achieving subcellular targeting. We showed that this platform profoundly restored SERCA activity, augmented cardiac function, and ameliorated adverse heart remodeling. Our study provides insight into the direct restoration of SR for the effective treatment of MIRI and other muscle diseases.

SERCA2, a P-type ATPase located on the endoplasmic reticulum of cells, plays an important role in maintaining calcium balance within cells by transporting calcium from the cytoplasm to the endoplasmic reticulum against its concentration gradient. A multitude of studies have demonstrated that the expression of SERCA2 is abnormal in a wide variety of tumor cells. Consequently, research exploring compounds that target SERCA2 may offer a promising avenue for the development of novel anti-tumor drugs. This review has summarized the anti-tumor compounds targeting SERCA2, including thapsigargin, dihydroartemisinin, curcumin, galangin, etc. These compounds interact with SERCA2 on the endoplasmic reticulum membrane, disrupting intracellular calcium ion homeostasis, leading to tumor cell apoptosis, autophagy and cell cycle arrest, ultimately producing anti-tumor effects. Additionally, several potential research directions for compounds targeting SERCA2 as clinical anti-cancer drugs have been proposed in the review. In summary, SERCA2 is a promising anti-tumor target for drug discovery and development.

Diabetes is a major risk factor for cardiovascular disease. However, the exact mechanism by which diabetes contributes to vascular damage is not fully understood. The aim of this study was to investigate the role of SUMO-1 mediated SERCA2a SUMOylation in the development of atherosclerotic vascular injury associated with diabetes mellitus. ApoE-/- mice were treated with streptozotocin (STZ) injection combined with high-fat feeding to simulate diabetic atherosclerosis and vascular injury. Human aortic vascular smooth muscle cells (HAVSMCs) were treated with high glucose (HG, 33.3 mM) and palmitic acid (PA, 200 µM) for 24 h to mimic a model of diabetes-induced vascular injury in vitro. Aortic vascular function, phenotypic conversion, migration, proliferation, intracellular Ca2+ concentration, the levels of small ubiquitin-like modifier type 1 (SUMO1), SERCA2a and SUMOylated SERCA2a were detected. Diabetes-induced atherosclerotic mice presented obvious atherosclerotic plaques and vascular injury, companied by significantly lower levels of SUMO1 and SERCA2a in aorta. HG and PA treatment in HAVSMCs reduced the expressions of SUMO1, SERCA2a and SUMOylated SERCA2a, facilitated the HAVSMCs phenotypic transformation, proliferation and migration, attenuated the Ca2+ transport, and increased the resting intracellular Ca2+ concentration. We also confirmed that SUMO1 directly bound to SERCA2a in HAVSMCs. Overexpression of SUMO1 restored the function and phenotypic contractile ability of HAVSMCs by upregulating SERCA2a SUMOylation, thereby alleviating HG and PA-induced vascular injury. These observations suggest an essential role of SUMO1 to protect diabetes-induced atherosclerosis and aortic vascular injury by the regulation of SERCA2a-SUMOylation and calcium homeostasis.

The cardiovascular sarcoplasmic reticulum (SR) calcium (Ca2+) ATPase is an imperative determinant of cardiac functionality. In addition, anomalies in Ca2+ handling protein and atypical energy metabolism are inherent in heart failure (HF). Moreover, Ca2+ overload in SR leads to mitochondrial matrix Ca2+ overload, which can trigger the generation of Reactive Oxygen Species (ROS), culminating in the triggering of the Permeability Transition Pore (PTP) and Cytochrome C release, resulting in apoptosis that leads to arrhythmias and numerous disorders. Although proteins involved in the molecular mechanism of Ca2+ dysfunction regarding mitochondrial dysfunction remains elusive, this study aims to assess the major Ca2+ handling proteins which may be involved in the Ca2+ malfunction that causes mitochondrial dysfunction and predicting the most effective drug by targeting the analyzed Ca2+ handling proteins through various insilico analyses. Thirteen proteins absorbed from interaction analysis were docked with four optimal phytochemicals from Crataegus oxyacantha (COC). Furthermore, The ADME profile of tyramine, vitexin, Epicatechin, and Epicatechin gallate was acclimated to evaluate potential drugability utilizing QikProp. So, molecular docking evaluations were performed using Glide (Maestro), autodock, and vina. Based on the results of 156 dockings by Maestro, auto-dock, and auto-dock vina, PKAC-a with Epicatechin gallate exhibits good interaction. Therefore, a 2000 ns molecular dynamics (MD) simulation was utilized to assess the feasible phytochemical Epicatechin gallate - PKAC-a complex binding stability utilizing Desmond and this study confirmed that Epicatechin gallate from COC has high possibilities to inhibit the aberrant cardiac Ca2+ signaling proteins due to its conformational rigidity.

An ellagitannin-derived metabolite, Urolithin A (UA), has emerged as a potential therapeutic agent for metabolic disorders due to its antioxidant, anti-inflammatory, and mitochondrial function-improving properties, but its efficacy in protecting against ER stress remains underexplored. The endoplasmic reticulum (ER) is a cellular organelle involved in protein folding, lipid synthesis, and calcium regulation. Perturbations in these functions can lead to ER stress, which contributes to the development and progression of metabolic disorders such as metabolic-associated fatty liver disease (MAFLD). In this study, we identified a novel target protein of UA and elucidated its mechanism for alleviating palmitic acid (PA)-induced ER stress. Cellular thermal shift assay (CETSA)-LC-MS/MS analysis revealed that UA binds directly to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), an important regulator of calcium homeostasis in mitochondria-associated ER membranes (MAMs). As an agonist of SERCA, UA attenuates abnormal calcium fluctuations and ER stress in PA-treated liver cells, thereby contributing to cell survival. The lack of UA activity in SERCA knockdown cells suggests that UA regulates cellular homeostasis through its interaction with SERCA. Collectively, our results demonstrate that UA protects against PA-induced ER stress and enhances cell survival by regulating calcium homeostasis in MAMs through SERCA. This study highlights the potential of UA as a therapeutic agent for metabolic disorders associated with ER stress.

β-adrenergic receptors (βARs) play significant roles in regulating Ca2+ signaling in cardiac myocytes, thus holding a key function in modulating heart performance. βARs regulate the influx of extracellular Ca2+ and the release and uptake of Ca2+ from the sarcoplasmic reticulum (SR) by activating key components such as L-type calcium channels (LTCCs), ryanodine receptors (RyRs) and phospholamban (PLN), mediated by the phosphorylation actions by protein kinase A (PKA). In cardiac myocytes, the presence of β2AR provides a protective mechanism against potential overstimulation of β1AR, which may aid in the restoration of cardiac dysfunctions. Understanding the Ca2+ regulatory signaling pathways of βARs in cardiac myocytes and the differences among various βAR subtypes are crucial in cardiology and hold great potential for developing treatments for heart diseases.

The prolonged overstimulation of β-adrenergic receptors (β-ARs), a member of the G protein-coupled receptor (GPCR) family, causes abnormalities in the density and functionality of the receptor and contributes to cardiac dysfunctions, leading to the development and progression of heart diseases, especially heart failure (HF). Despite recent advancements in HF therapy, mortality and morbidity rates continue to be high. Treatment with β-AR antagonists (β-blockers) has improved clinical outcomes and reduced overall hospitalization and mortality rates. However, several barriers in the management of HF remain, providing opportunities to develop new strategies that focus on the functions and signal transduction of β-ARs involved in the pathogenesis of HF. As β-AR can signal through multiple pathways influenced by different receptor subtypes, expression levels, and signaling components such as G proteins, G protein-coupled receptor kinases (GRKs), β-arrestins, and downstream effectors, it presents a complex mechanism that could be targeted in HF management. In this narrative review, we focus on the regulation of β-ARs at the receptor, G protein, and effector loci, as well as their signal transductions in the physiology and pathophysiology of the heart. The discovery of potential ligands for β-AR that activate cardioprotective pathways while limiting off-target signaling is promising for the treatment of HF. However, applying findings from preclinical animal models to human patients faces several challenges, including species differences, the genetic variability of β-ARs, and the complexity and heterogeneity of humans. In this review, we also summarize recent updates and future research on the regulation of β-ARs in the molecular basis of HF and highlight potential therapeutic strategies for HF.

A better understanding of the underlying pathomechanisms of diastolic dysfunction is crucial for the development of targeted therapeutic options with the aim to increase the patients' quality of life. In order to shed light on the processes involved, suitable models are required. Here, effects of endothelin-1 (ET-1) treatment on cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were investigated. While it is well established, that ET-1 treatment induces hypertrophy in cardiomyocytes, resulting changes in cell mechanics and contractile behavior with focus on relaxation have not been examined before. Cardiomyocytes were treated with 10 nM of ET-1 for 24 h and 48 h, respectively. Hypertrophy was confirmed by real-time deformability cytometry (RT-DC) which was also used to assess the mechanical properties of cardiomyocytes. For investigation of the contractile behavior, 24 h phase contrast video microscopy was applied. To get a deeper insight into changes on the molecular biological level, gene expression analysis was performed using the NanoString nCounter® cardiovascular disease panel. Besides an increased cell size, ET-1 treated cardiomyocytes are stiffer and show an impaired relaxation. Gene expression patterns in ET-1 treated hiPSC derived cardiomyocytes showed that pathways associated with cardiovascular diseases, cardiac hypertrophy and extracellular matrix were upregulated while those associated with fatty acid metabolism were downregulated. We conclude that alterations in cardiomyocytes after ET-1 treatment go far beyond hypertrophy and represent a useful model for diastolic dysfunction.

Specific protein 1 (Sp1) is pivotal in sustaining baseline transcription as well as modulating cell signaling pathways and transcription factors activity. Through interactions with various proteins, especially transcription factors, Sp1 controls the expression of target genes, influencing numerous biological processes. Numerous studies have confirmed Sp1's significant regulatory role in the pathogenesis of cardiovascular disorders. Post-translational modifications (PTMs) of Sp1, such as phosphorylation, ubiquitination, acetylation, glycosylation, SUMOylation, and S-sulfhydration, can enhance or modify its transcriptional activity and DNA-binding stability. These modifications also regulate Sp1 expression across different cell types. Sp1 is crucial in regulating non-coding gene expression and the activity of proteins in response to pathophysiological stimuli. Understanding Sp1 PTMs advances our knowledge of cell signaling pathways in controlling Sp1 stability during cardiovascular disease onset and progression. It also aids in identifying novel pharmaceutical targets and biomarkers essential for preventing and managing cardiovascular diseases.

Heterochronic parabiosis consists of surgically connecting the circulatory systems of a young and an old animal. This technique serves as a model to study circulating factors that accelerate aging in young organisms exposed to old blood or induce rejuvenation in old organisms exposed to young blood. Despite the promising results, the exact cellular and molecular mechanisms remain unclear, so this study aims to explore and elucidate them in more detail.

Activin A (Act A) is a member of the TGFβ (transforming growth factor β) superfamily. It communicates via the Suppressor of Mothers against Decapentaplegic Homolog (SMAD2/3) proteins which govern processes such as cell proliferation, wound healing, apoptosis, and metabolism. Act A produces its action by attaching to activin receptor type IIA (ActRIIA) or activin receptor type IIB (ActRIIB). Increasing circulating Act A increases ActRII signalling, which on phosphorylation initiates the ALK4 (activin receptor-like kinase 4) type 1 receptor which further turns on the SMAD pathway and hinders cell functioning. Once triggered, this route leads to gene transcription, differentiation, apoptosis, and extracellular matrix (ECM) formation. Act A also governs the immunological and inflammatory responses of the body, as well as cell death. Moreover, Act A levels have been observed to elevate in several disorders like renal fibrosis, CKD, asthma, NAFLD, cardiovascular diseases, cancer, inflammatory conditions etc. Here, we provide an update on the recent studies relevant to the role of Act A in the modulation of various pathological disorders, giving an overview of the biology of Act A and its signalling pathways, and discuss the possibility of incorporating activin-A targeting as a novel therapeutic approach for the control of various disorders. Pathways such as SMAD signaling, in which SMAD moves to the nucleus by making a complex and leads to tissue fibrosis in CKD, STAT3, which drives renal fibroblast activity and the production of ECM, Kidney injury molecule (KIM-1) in the synthesis, deposition of ECM proteins, SERCA2a (sarcoplasmic reticulum Ca2+ ATPase) in cardiac dysfunction, and NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) in inflammation are involved in Act A signaling, have also been discussed.

In mammals, specificity protein 1 (SP1) was the first Cys2-His2 zinc finger transcription factor to be isolated within the specificity protein and Krüppel-like factor (Sp/KLF) gene family. SP1 regulates gene expression by binding to Guanine-Cytosine (GC)-rich sequences on promoter regions of target genes, affecting various cellular processes. Additionally, the activity of SP1 is markedly influenced by posttranslational modifications, such as phosphorylation, acetylation, glycosylation, and proteolysis. SP1 is implicated in the regulation of apoptosis, cell hypertrophy, inflammation, oxidative stress, lipid metabolism, plaque stabilization, endothelial dysfunction, fibrosis, calcification, and other pathological processes. These processes impact the onset and progression of numerous cardiovascular disorders, including coronary heart disease, ischemia-reperfusion injury, cardiomyopathy, arrhythmia, and vascular disease. SP1 emerges as a potential target for the prevention and therapeutic intervention of cardiac ailments. In this review, we delve into the biological functions, pathophysiological mechanisms, and potential clinical implications of SP1 in cardiac pathology to offer valuable insights into the regulatory functions of SP1 in heart diseases and unveil novel avenues for the prevention and treatment of cardiovascular conditions.

Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.

The correlation between hematopoietic cell-specific lyn substrate 1 (HCLS1) expression levels and heart failure (HF) remains unclear. HF datasets GSE192886 and GSE196656 profiles were generated from GPL24676 and GPL20301 platforms in gene expression omnibus (GEO) database and differentially expressed genes (DEGs) were obtained, which was followed by weighted gene co-expression network analysis, protein-protein interaction (PPI) networks, functional enrichment analysis and comparative toxicogenomics database (CTD) analysis. Heatmaps of gene expression levels were plotted. TargetScan was used to screen miRNAs regulating central DEGs. A total of 500 DEGs were found and mainly concentrated in leukocyte activation, protein phosphorylation, and protein complexes involved in cell adhesion, PI3K Akt signaling pathway, Notch signaling pathway, and right ventricular cardiomyopathy. PPI network identified 15 core genes (HCLS1, FERMT3, CD53, CD34, ITGAL, EP300, LYN, VAV1, ITGAX, LEP, ITGB1, IGF1, MMP9, SMAD2, RAC2). Heatmap shows that 4 genes (EP300, CD53, HCLS1, LYN) are highly expressed in HF tissue samples. We found that 4 genes (EP300, CD53, HCLS1, LYN) were associated with heart diseases, cardiovascular diseases, edema, rheumatoid arthritis, necrosis, and inflammation. HCLS1 is highly expressed in HF and maybe its target.

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N-acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy.

RNA binding proteins (RBPs) play a central in the post-transcriptional regulation of gene expression, which can account for up to 50% of all variations in protein expression within a cell. Following their binding to target RNAs, RBPs most typically confer changes in gene expression through modulation of alternative spicing, RNA stabilization/degradation, or ribosome loading/translation rate. All of these post-transcriptional regulatory processes have been shown to play a functional role in pathological cardiac remodeling, and a growing body of evidence is beginning to identify the mechanistic contribution of individual RBPs and their cardiac RNA targets. This review highlights the mechanisms of RBP-dependent post-transcriptional gene regulation in cardiomyocytes and fibroblasts and our current understanding of how RNA binding proteins functionally contribute to pathological cardiac remodeling.

Interleukin-37 (IL-37) is a potent anti-inflammatory cytokine belonging to the IL-1 family. This study investigates the regulatory mechanism and reparative effects of IL-37 on HF-related human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) and engineered human heart tissue subjected to hypoxia and H2O2 treatment. The contractile force and Ca2+ conduction capacity of the tissue are assessed using a stretching platform and high-resolution fluorescence imaging system. This investigation reveals that IL-37 treatment significantly enhances cell viability, calcium transient levels, contractile force, and Ca2+ conduction capacity in HF-related hiPSC-CMs and engineered human heart tissue. Notably, IL-37 facilitates the upregulation of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) through enhancing nuclear p-STAT3 levels. This effect is mediated by the binding of p-STAT3 to the SERCA2a promoter, providing a novel insight on the reparative potential of IL-37 in HF. IL-37 demonstrates its ability to enhance systolic function by modulating myocardial calcium handling via the p-STAT3/SERCA2a axis in HF-related engineered human heart tissue (as shown in schematic diagram).

Calcium homeostasis imbalance is one of the important pathological mechanisms in heart failure. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), a calcium ATPase on the sarcoplasmic reticulum in cardiac myocytes, is a myocardial systolic-diastolic Ca2 + homeostasis regulating enzyme that is not only involved in cardiac diastole but also indirectly affects cardiac myocyte contraction. SERCA2a expression was found to be decreased in myocardial tissue in heart failure, however, there are few reports on serum SERCA2a expression in patients with heart failure, and this study was designed to investigate whether serum SERCA2a levels are associated with the occurrence of adverse events after discharge in patients hospitalized with heart failure. Patients with heart failure hospitalized in the cardiovascular department of the Second Affiliated Hospital of Guangdong Medical University, China, from July 2018 to July 2019 were included in this study, and serum SERCA2a concentrations were measured; each enrolled patient was followed up by telephone after 6 months (6 ± 1 months) for general post-discharge patient status. The correlation between serum SERCA2a levels and the occurrence of adverse events (death or readmission due to heart failure) after hospital discharge was assessed using multiple analysis and trend analysis. Seventy-one patients with heart failure were finally included in this study, of whom 38 (53.5%) were men and 33 (46.5%) were women (All were postmenopausal women). Multiple analysis revealed no correlation between serum SERCA2a levels and the occurrence of adverse events in the total study population and in male patients, but serum SERCA2a levels were associated with the occurrence of adverse outcome events after hospital discharge in female patients (OR = 1.02, P = .047). Further analysis using a trend analysis yielded a 4.0% increase in the risk of adverse outcomes after hospital discharge for each unit increase in SERCA2a in female patients (OR = 1.04; P = .02), while no significant difference was seen in men. This study suggests that serum SERCA2a levels at admission are associated with the occurrence of post-discharge adverse events in postmenopausal female patients hospitalized with heart failure.

The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria and targeted treatment approaches in clinical practice. Ongoing research is gradually unravelling the pathogenesis of diabetic cardiomyopathy, with a particular emphasis on investigating various post-translational modifications. These modifications dynamically regulate protein function in response to changes in the internal and external environment, and their disturbance of homeostasis holds significant relevance for the development of chronic ailments. This review provides a comprehensive overview of the common post-translational modifications involved in the initiation and progression of diabetic cardiomyopathy, including O-GlcNAcylation, phosphorylation, methylation, acetylation and ubiquitination. Additionally, the review discusses drug development strategies for targeting key post-translational modification targets, such as agonists, inhibitors and PROTAC (proteolysis targeting chimaera) technology that targets E3 ubiquitin ligases.

Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD.

We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF.

Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice.

Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes' (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). Right heart disease and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. We hypothesized that right heart disease generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility.

Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275 g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, connexin-43 levels, and CM morphology. Right atrial levels of selected genes and proteins were obtained by qPCR and Western blot, respectively. Pulmonary artery banding induced severe RHD identified by RV and RA hypertrophy. Pulmonary artery banding rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated and hypercontractile. Right atrial CM from PAB animals showed significant augmentation of mRNA and protein levels of pro-inflammatory interleukin (IL)-6 and IL1β. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) and junctophilin-2 were decreased in RA CM from PAB compared to sham rats.

Right heart disease-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.