Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation

Wang, Dongxiao; Huang, Zheng; Li, Qingjie; Zhong, Guoqiang; He, Yan; Huang, Weiqiang; Cao, Xiaoli; Tu, Rong‐Hui; Meng, Jianjun

doi:10.1590/s0102-865020200010000005

Cited by 14 publications

(15 citation statements)

References 31 publications

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“…This was consistent with the findings of Sugiura et al ( 28 ), which showed that in an ischemic acute kidney injury model, klotho inhibited apoptosis via Hsp70. Previously, Hsp90 was found to exert a profound ischemic postconditioning cardioprotective effect and to alleviate I/R-induced myocardial injury and apoptosis in vivo ( 36 ). Notably, the western blotting results of the present study showed that klotho overexpression in H9c2(2-1) cells prior to H/R treatment upregulated the levels of p-Akt and p-Bad.…”

Section: Discussionmentioning

confidence: 99%

Klotho overexpression suppresses apoptosis by regulating the Hsp70/Akt/Bad pathway in H9c2(2-1) cells

Su²,

et al. 2021

Exp Ther Med

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Early reperfusion is the most effective and important treatment for acute myocardial infarction. However, reperfusion therapy often leads to a certain degree of myocardial damage. The aim of the present study was to identify the role of klotho, and the molecular mechanism underlying its effects, in myocardial damage using a model of myocardial hypoxia injury. Hypoxia/reoxygenation (H/R) was used to mimic ischemia/reperfusion (I/R) injury in vitro . The expression and distribution of klotho in H9c2(2-1) cells was observed by fluorogenic scanning, and the apoptotic rate was determined by Annexin V-FITC/propidium iodide dual staining. Cell viability was determined by MTT assay, and caspase-3, cleaved caspase-3, Bcl-2, Bax, heat shock protein (Hsp) 70 and Akt levels were assessed by western blotting. A lactate dehydrogenase test was performed to determine the degree of H9c2(2-1) cell damage. The results revealed that klotho was primarily located in the cytoplasm of H9c2(2-1) cells. Klotho overexpression markedly suppressed H/R-induced H9c2(2-1) cell apoptosis. Furthermore, cell viability increased, and injury decreased in response to klotho. Klotho also suppressed the activation of caspase-3, upregulated Bcl2 and decreased Bax levels following H/R injury, as well as alleviating H/R injury by upregulating the expression of Hsp70 and increasing the levels of phosphorylated (p-)Akt and Bad. In conclusion, these results indicate that klotho suppressed H/R-induced H9c2(2-1) cell apoptosis by regulating the levels of Hsp70, p-Akt and p-Bad, which suggest that klotho could be a novel agent for the treatment of coronary disease.

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Section: Discussionmentioning

confidence: 99%

Klotho overexpression suppresses apoptosis by regulating the Hsp70/Akt/Bad pathway in H9c2(2-1) cells

Su²,

et al. 2021

Exp Ther Med

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“…In unstressed cells, the HSF1 monomer is retained in the cytoplasm in a complex with HSP40, HSP70, and HSP90, as well as the TRiC [ 20 ]. The decrease in HSF1 protein levels may lead to the increase of unbound chaperone proteins including HSP90, which in turn plays roles in suppressing the expression of C3 and inflammatory cytokines, as shown in ischemic postconditioning-induced cardioprotection [ 48 ]. However, the postulation needs to be further clarified.…”

Section: Discussionmentioning

confidence: 99%

HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats

et al. 2021

J Neuroinflammation

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Background Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). A1 astrocytes are known to be neurotoxic that participate in neuropathogenesis, whereas A2 astrocytes have been assigned the neuroprotective activity. Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation. It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI. Methods A contusion model of the rat spinal cord was established, and the correlations between HSF1 expression and onset of A1 and A2 astrocytes were assayed by Western blot and immunohistochemistry. 17-AAG, the agonist of HSF1, was employed to treat the primary cultured astrocytes following a challenge by an A1-astrocyte-conditioned medium (ACM) containing 3 ng/ml of IL-1α, 30 ng/ml of TNF-α, and 400 ng/ml of C1q for induction of the A1 subtype. The effects of 17-AAG on the phenotype conversion of astrocytes, as well as underlying signal pathways, were examined by Western blot or immunohistochemistry. Results The protein levels of HSF1 were significantly increased at 4 days and 7 days following rat SCI, showing colocalization with astrocytes. Meanwhile, C3-positive A1 astrocytes were observed to accumulate at lesion sites with a peak at 1 day and 4 days. Distinctively, the S100A10-positive A2 subtype reached its peak at 4 days and 7 days. Incubation of the primary astrocytes with ACM markedly induced the conversion of the A1 phenotype, whereas an addition of 17-AAG significantly suppressed such inducible effects without conversion of the A2 subtype. Activation of HSF1 remarkably inhibited the activities of MAPKs and NFκB, which was responsible for the regulation of C3 expression. Administration of 17-AAG at the lesion sites of rats was able to reduce the accumulation of A1 astrocytes. Conclusion Collectively, these data reveal a novel mechanism of astrocyte phenotype conversion following SCI, and HSF1 plays key roles in suppressing excessive increase of neurotoxic A1 astrocytes.

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“…Activated by cellular stress, HSP90 plays a central role in myocardial I/R injury and cardioprotection during ischemic preconditioning and pharmacological conditioning [ 5 , 7 , 25 ]. Our laboratory recently found the important role of HSP90 in postconditioning [ 6 , 19 , 26 , 27 ]. HSP90, especially in the mitochondria, facilitates translocation of mitochondria proteins in cardioprotection against I/R-induced injury.…”

Section: Discussionmentioning

confidence: 99%

New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB

Wang

Zhong

et al. 2021

Open Medicine

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Background Activation of the complement component 5a (C5a) and nuclear factor κB (NF-κB) signaling is an important feature of myocardial ischemia/reperfusion (I/R) injury and recent studies show that morphine postconditioning (MP) attenuates the myocardial injury. However, the mediating cardioprotective mechanisms remain unclear. The present study explores the role and interaction of heat shock protein 90 (HSP90), Akt, C5a, and NF-κB in MP-induced cardioprotection. Methods Male Sprague Dawley rats (n = 160) were randomized into eight groups (n = 20 per group). Rats in the sham group underwent thoracotomy, passing the ligature through the heart but without tying it (150 min), and the other seven groups were subjected to 30 min of anterior descending coronary artery occlusion followed by 2 h of reperfusion and the following treatments: I/R (30 min of ischemia and followed by 2 h of reperfusion); ischemic postconditioning (IPostC, 30 s of ischemia altered with 30 s of reperfusion, repeated for three cycles, and followed by reperfusion for 2 h); MP (0.3 mg/kg morphine administration 10 min before reperfusion); MP combined with the HSP90 inhibitor geldanamycin (GA, 1 mg/kg); MP combined with the Akt inhibitor GSK-690693 (GSK, 20 mg/kg); and MP combined with the C5a inhibitor PMX205 (PMX, 1 mg/kg/day, administration via drinking water for 28 days) and MP combined with the NF-κB inhibitor EVP4593 (QNZ, 1 mg/kg). All inhibitors were administered 10 min before morphine and followed by 2 h reperfusion. Results MP significantly reduced the I/R-induced infarct size, the apoptosis, and the release of cardiac troponin I, lactate dehydrogenase (LDH), and creatine kinase-MB. These beneficial effects were accompanied by increased expression of HSP90 and p-Akt, and decreased expression of C5a, NF-κB, tumor necrosis factor α, interleukin-1β, and intercellular cell adhesion molecule 1. However, HSP90 inhibitor GA or Akt inhibitor GSK increased the expression of C5a and NF-κB and prevented MP-induced cardioprotection. Furthermore, GA inhibited the MP-induced upregulation of p-Akt, while GSK did not affect HSP90, indicating that p-Akt acts downstream of HSP90 in MP-induced cardioprotection. In addition, C5a inhibitor PMX enhanced the MP-induced downregulation of NF-κB, while NF-κB inhibitor QNZ had no effect on C5a, indicating that the C5a/NF-κB signaling pathway is involved in MP-induced cardioprotection. Conclusion HSP90 is critical for MP-mediated cardioprotection possibly by promoting the phosphorylation of Akt and inhibiting the activation of C5a and NF-κB signaling and the subsequent myocardial inflammation, ultimately attenuating the infarct size and cardiomyocyte apoptosis.

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Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation

Cited by 14 publications

References 31 publications

Klotho overexpression suppresses apoptosis by regulating the Hsp70/Akt/Bad pathway in H9c2(2-1) cells

Klotho overexpression suppresses apoptosis by regulating the Hsp70/Akt/Bad pathway in H9c2(2-1) cells

HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats

New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB

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