Research Article: Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation1

Date Published: March 20, 2020

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia

Author(s): Dong-Xiao Wang, Zheng Huang, Qing-Jie Li, Guo-Qiang Zhong, Yan He, Wei-Qiang Huang, Xiao-Li Cao, Rong-Hui Tu, Jian-Jun Meng.


To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC).

The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β and c-Jun N-terminal kinase (JNK) were assessed.

Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1β, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA.

HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.

Partial Text

Ischemic reperfusion injury caused by early reperfusion in the treatment of acute myocardial infarction often aggravates myocardial cell damage and further worsens the prognosis of patients1,2. Activation of the complement system is an important feature of ischemia-reperfusion (I/R) injury, and has received increasing attention3,4.

This study was conducted at the Experimental Animal Center of Guangxi Medical University. All experimental protocols used in this study were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Guangxi Medical University Animal Protection and Use Committee.

Eighty rats were used in the present study. Due to the cardiogenic shock during the reperfusion and ventilator technical failure, three rats were excluded: One of them belonged to the IPC group and died unexplained, and the remaining two (one in the I/R group and one in the IPC + GA group) were excluded because of cardiogenic shock or tracheal obstruction. The presented results correspond to the remaining 77 rats.

In the present study, we explored the role and potential mechanisms of HSP90 and the complement system in IPC. We found that IPC significantly reduced the I/R-induced complement system and JNK activation by up-regulating the expression of HSP90, leading to further reductions in the myocardial infarction area, cardiomyocyte apoptosis, the release of cTnT, CK-MB and LDH, and the release of inflammatory mediators such as TNF-α and IL-1β, whereas, treatment with GA reversed the protection of IPC. Thus, it was proven for the first time that HSP90 is essential for inhibiting cardiac complement and immune inflammatory responses in IPC, possibly by inhibiting complement system activation and JNK. Our data reveal a novel mechanism of IPC cardioprotection.

HSP90 exerts a profound effect on IPC cardioprotection, and its function may be linked to the inhibition of complement system, JNK and inflammatory responses, ultimately attenuating I/R-induced myocardial injury and apoptosis. Our observations complement the literature on IPC-related cardiac protection against I/R




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