# 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

## TL;DR

Vericiguat protects the heart from injury during reperfusion by acting through heat shock protein 90, which reduces inflammation and cell death.

## Contribution

This study identifies HSP90 as a mediator of vericiguat's cardioprotective effects via TLR4 and JNK inhibition.

## Key findings

- Vericiguat reduced myocardial infarct size and apoptosis in mice with ischemia-reperfusion injury.
- HSP90 inhibition reversed the protective effects of vericiguat, suggesting its mediating role.
- Vericiguat decreased TLR4, JNK activation, and inflammatory markers while increasing Bcl-2 expression.

## Abstract

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.

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.

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.

HSP90 mediates the cardioprotective effects of vericiguat, potentially by inhibiting TLR4, JNK activation, and inflammatory responses.