Heat shock protein 90 mediates the protective effects of vericiguat on myocardial ischemia/reperfusion injury by inhibiting toll-like receptor 4 and c-Jun N-terminal kinases

Articles in Press

Document Type : Original Article

Authors

1 Department of Cardiology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China

2 Department of Geriatric Cardiology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China

3 Guang Xi Key laboratory of Precision Medicine in Cardio-cerebrovascular Disease Control and Prevention, Nanning 530021, Guangxi, China

4 Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China

10.22038/ijbms.2025.84354.18248

Abstract

Objective(s): This study aimed to investigate whether vericiguat exerts a protective effect against myocardial ischemia-reperfusion injury (MIRI) by inhibiting toll-like receptor 4 (TLR4) and c-Jun N-terminal kinases (JNK) activation and whether heat shock protein 90 (HSP90) mediates these effects.
Materials and Methods: A total of 120 male mice were randomly divided into six groups: sham, ischemia/reperfusion (I/R group), VPreC (vericiguat, 3 mg/kg, administered intravenously 12 hr before ligation), VPreC+HSP90 inhibitor geldanamycin (GA) (geldanamycin, 1 mg/kg, injected intraperitoneally 30 min before ligation), VPostC (vericiguat, 3 mg/kg, administered intravenously ten minutes before reperfusion), and VPostC+GA (geldanamycin, 1 mg/kg, injected intraperitoneally 20 min before reperfusion). The remaining five groups were subjected to 30 min of ischemia followed by two hours of reperfusion. The sizes of myocardial infarction, rates of cardiomyocyte apoptosis, and levels of myocardial markers were measured. In addition, the protein expressions of HSP90, TLR4, JNK, BAX, and B-lymphoblastoma-2 (Bcl-2) were detected, along with the mRNA levels of inflammatory factors.
Results: Vericiguat significantly reduced I/R-induced myocardial infarct size, apoptosis rate, and myocardial marker release. Alongside these positive effects, there was an increase in HSP90 and Bcl-2 expression, as well as a decrease in TLR4, JNK, BAX expression, and inflammatory factor levels. However, the HSP90 inhibitor GA reversed these protective and anti-inflammatory effects.
Conclusion: HSP90 mediates the cardioprotective effects of vericiguat, potentially by inhibiting TLR4, JNK activation, and inflammatory responses.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences

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Available Online from 18 May 2025

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