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. 2025;28(9):1220-1229.
doi: 10.22038/ijbms.2025.84354.18248.

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

Si-Jie Pan  1 , Jun-Yan Chen  1 , Dong-Xiao Wang  1 , Jian-Jun Meng  2 , Min Wang  2 , Guo-Qiang Zhong  1   3   4 , Zhi-Yu Zeng  1   3   4 , Rong-Hui Tu  2   3   4
Affiliations

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

Si-Jie Pan et al. Iran J Basic Med Sci. 2025.

Abstract

Objectives: 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: HSP90; Ischemic postconditioning Ischemic preconditioning JNK; TLR4; Vericiguat.

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Conflict of interest statement

The authors declared no potential conflicts of interest regarding the research, authorship, and publication of this article.

Figures

Figure 1
Figure 1
Schematic diagrams of different experimental treatments for each group
Figure 2
Figure 2
Effects of Vericiguat and Vericiguat+geldanamycin (GA) on HSP90 protein expression levels after myocardial ischemia/reperfusion injury in mice
Figure 3
Figure 3
Effect of Vericiguat and Vericiguat+geldanamycin (GA) on myocardial infarct area after myocardial ischemia-reperfusion injury in mice
Figure 4
Figure 4
Effect of Vericiguat and Vericiguat+geldanamycin (GA) on apoptosis after myocardial ischemia-reperfusion injury in mice (×400 magnification, bar=20 μm)
Figure 5
Figure 5
Effects of Vericiguat and Vericiguat+geldanamycin (GA) on mRNA levels of IL-6, ICAM-1, and TNF-α after myocardial ischemia/reperfusion injury in mice
Figure 6
Figure 6
Effects of Vericiguat and Vericiguat+geldanamycin (GA) on TLR4 and JNK protein expression levels after myocardial ischemia/reperfusion injury in mice
Figure 7
Figure 7
Effects of Vericiguat and Vericiguat+geldanamycin (GA) on Bax and Bcl-2 protein expression levels after myocardial ischemia/reperfusion injury in mice
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