Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. However, the molecular mechanisms underlying septic cardiomyopathy remain elusive. Irisin is a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) that protects the heart from ischemia/reperfusion injury through upregulation of mitochondrial ubiquitin ligase (MITOL). Gasdermin D (GSDMD)-dependent pyroptosis plays a pivotal role in septic cardiomyopathy by regulating mitochondrial homeostasis. However, whether irisin can regulate MITOL to inhibit GSDMD-dependent pyroptosis in septic cardiomyopathy is yet to be investigated. Thus, this study was designed to explore the role of irisin in septic cardiomyopathy and its underlying molecular mechanisms. Our results demonstrate that irisin improves cardiac function against sepsis-induced cardiac dysfunction by reducing cardiac inflammation and myocardial pyroptosis. Using MITOL siRNA in vitro, the results revealed that the protective role of irisin against lipopolysaccharide (LPS)-induced cell injury was mediated by MITOL activation and the resulting inhibition of GSDMD-dependent pyroptosis. Moreover, irisin alleviated LPS-induced H9c2 cell injury by suppressing IL-1β expression and reducing serum LDH and CK-MB concentrations in a MITOL/GSDMD-dependent manner. Collectively, our data suggest that irisin treatment ameliorates cardiac dysfunction in septic cardiomyopathy by activating MITOL and inhibiting GSDMD-dependent pyroptosis. These findings highlight the clinical relevance and therapeutic potential of irisin and MITOL for the management of sepsis-induced cardiac dysfunction.

Objective: Estrogen is indispensable in health and disease and mainly functions through its receptors. The protection of the cardiovascular system by estrogen and its receptors has been recognized for decades. Numerous studies with a focus on estrogen and its receptor system have been conducted to elucidate the underlying mechanism. Although nuclear estrogen receptors, including estrogen receptor-α and estrogen receptor-β, have been shown to be classical receptors that mediate genomic effects, studies now show that GPER mainly mediates rapid signaling events as well as transcriptional regulation via binding to estrogen as a membrane receptor. With the discovery of selective synthetic ligands for GPER and the utilization of GPER knockout mice, significant progress has been made in understanding the function of GPER. In this review, the tissue and cellular localizations, endogenous and exogenous ligands, and signaling pathways of GPER are systematically summarized in diverse physiological and diseased conditions. This article further emphasizes the role of GPER in vascular pathology and physiology, focusing on the latest research progress and evidence of GPER as a promising therapeutic target in hypertension, pulmonary hypertension, and atherosclerosis. Thus, selective regulation of GPER by its agonists and antagonists have the potential to be used in clinical practice for treating such diseases.

Cardiac dysfunction caused by sepsis is the predominant reason for death in patients with sepsis. However, the effective drugs for its prevention and the molecular mechanisms remain elusive. 1-Deoxynojirimycin (DNJ), a natural iminopyranose, exhibits various biological properties, such as hypoglycemic, antitumor, antiviral, and anti-inflammatory activities. However, whether DNJ can mediate biological activity resistance in sepsis-induced myocardial injury and the underlying mechanisms are unclear. Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling is an important pathway for the signal transduction of several key cytokines in the pathogenesis of sepsis, which can transcribe and modulate the host immune response. This study was conducted to confirm whether DNJ mediates oxidative stress, apoptosis, and inflammation in cardiomyocytes, thereby alleviating myocardial injury in sepsis via the JAK2/STAT6 signaling pathway. Septic cardiomyopathy was induced in mice using lipopolysaccharide (LPS), and they were then treated with DNJ. The results showed that DNJ markedly improved sepsis-induced cardiac dysfunction, attenuated reactive oxygen species generation, reduced cardiomyocyte apoptosis, and mitigated inflammation. Mechanistically, increased JAK2/STAT6 phosphorylation was observed in the mouse sepsis models, which decreased significantly after DNJ oral treatment. To further confirm whether DNJ mediates the JAK2/STAT6 pathway, the selective inhibitor fedratinib was used to block the JAK2 signaling pathway in vitro, which enhanced the protective effects of DNJ against the sepsis-induced cardiac damage. Collectively, these findings suggest that DNJ attenuates sepsis-induced myocardial injury by decreasing myocardial oxidative damage, apoptosis, and inflammation via the regulation of the JAK2/STAT6 signaling pathway.

Rationale: Sepsis-induced cardiomyopathy (SIC) is a rapidly progressing condition with poor prognosis in the absence of effective therapeutic interventions. Cardiomyocyte pyroptosis is a critical factor contributing to cardiac dysfunction in SIC. Currently, research on this mechanism remains unclear.

Heart failure with preserved ejection fraction (HFpEF) is a major subtype of heart failure, primarily characterized by a normal or mildly reduced left ventricular ejection fraction along with left ventricular diastolic dysfunction. Recent studies have shown that the prevalence of HFpEF is higher in women than that in men, particularly in postmenopausal women. Concurrently, it has been observed that the incidence of risk factors contributing to HFpEF (such as obesity, hypertension, diabetes, and atrial fibrillation) also notably increases post-menopause, affecting the incidence of HFpEF. This review aimed to examine the relationship between estrogen and risk factors associated with HFpEF, clarifying the underlying mechanisms through which estrogen affects these risk factors from epidemiological and pathophysiological perspectives. This review also provides a comprehensive understanding of the association between estrogen and the risk factors for HFpEF, thus helping explore potential targets for HFpEF treatment.

Background: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in β-aminopropionitrile fumarate (BAPN)-induced TAD. Methods: A mouse model of TAD induced by BAPN and IL-1β -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. Results: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. Conclusion: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.