ABSTRACT
Our objective was to determine the role of acetyl-Hsp90 and its relationship with the NF-κB p65 signaling pathway in CVDs. We investigated the effect of acetyl-Hsp90 on cardiac inflammation and apoptosis after ischemia-reperfusion injury (I/RI). The results showed that the induction of acetyl-Hsp90 occurred in the heart during I/R and in primary cardiomyocytes during oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, the nonacetylated mutant of Hsp90 (Hsp90-K284R), through the regulation of ATPase activities within its N-terminal domain (NTD), indirectly or directly increases its interaction with NF-κB p65. This led to a reduction in the activation of the NF-κB p65 pathway, thereby attenuating inflammation, apoptosis, and fibrosis, ultimately leading to an improvement in cardiac function. Furthermore, we demonstrated that recombinant human interleukin-37 (rIL-37) exerts a similar cardioprotective effect by reducing acetylation at K284 of Hsp90 after inhibiting the expression of KAT2A.
ABSTRACT
Protein kinase C (PKC) plays a role in cardioprotection through reduction of intracellular Ca(2+) concentration [Ca(2+)](i) during ischemic preconditioning (IPC). Cardioprotection against ischemic post-conditioning (PC) could be associated with reduced [Ca(2+)](i) through PKC. The calcium-sensing receptor (CaR), G protein-coupled receptor, causes accumulation of inositol phosphate (IP) to increase the release of intracellular Ca(2+). However, this phenomenon can be negatively regulated by PKC through phosphorylation of Thr-888 of the CaR. This study tested the hypothesis that the prevention of cardiomyocyte damage by PC is associated with [Ca(2+)](i) reduction through an interaction of PKC with the CaR. Isolated rat hearts were subjected to 40min of ischemia followed by 90min of reperfusion. The hearts were post-conditioned after the 40min of ischemia by three cycles of 30s of reperfusion and 30s of re-ischemia applied before the 90min of reperfusion. Immunolocalization of PKCepsilon in the cell membrane was observed with IPC and PC, and in hearts exposed to GdCl(3) during PC. CaR was expressed in cardiac cell membrane and interacted with PKC in IPC, PC, and exposure to GdCl(3) during PC groups. On laser confocal microscopy, intracellular Ca(2+) was significantly decreased with IPC, PC, and exposure to GdCl(3) during PC compared with the I/R and PKC inhibitor groups, and cell structure was better preserved and promoted the recovery of cardiac function after reperfusion in the same groups. These results suggested that PKC is involved in cardioprotection against PC through negative feedback of a CaR-mediated reduction in [Ca(2+)](i).