Nicorandil inhibits cardiomyocyte apoptosis and improves cardiac function by suppressing the HtrA2/XIAP/PARP signaling after coronary microembolization in rats

Abstract

Cardiomyocyte apoptosis is a key factor in the deterioration of cardiac function after coronary microembolization (CME). Nicorandil (NIC) affects myocardial injury, which may be related to the inhibition of apoptosis. However, the specific mechanism of cardioprotection has not been elucidated. Therefore, we analyzed the impact of NIC on cardiac function in rats subjected to CME and its effect on the high‐temperature requirement peptidase 2/X‐linked inhibitor of apoptosis protein/poly ADP‐ribose polymerase (HtrA2/XIAP/PARP) pathway. Sprague Dawley rats were divided into four groups: Sham, CME, CME + NIC, and CME + UCF. Echocardiography was performed 9 hours after CME. Myocardial injury markers were evaluated in blood samples, and the heart tissue was collected for hematoxylin‐eosin staining, hematoxylin basic fuchsin picric acid staining staining, TdT‐mediated DUTP nick end labeling (TUNEL) staining, Western blot analysis of the HtrA2/XIAP/PARP pathway, and transmission electron microscopy. NIC ameliorated cardiac dysfunctioncaused by CME and reduced serum levels of CK‐MB and LDH. In addition, NIC decreased myocardial microinfarct size and apoptotic index. NIC reduced the Bax/Bcl‐2 ratio, levels of cleaved caspase 3/9, cytoplasmic HtrA2, and cleaved PARP, and increased the level of XIAP. The effects of NIC were similar to those of the HtrA2 inhibitor, UCF101. This study demonstrated that NIC reduces CME‐induced myocardial injury, reduces mitochondrial damage, and improves myocardial function. The reduction in cardiomyocyte apoptosis by NIC may be mediated by the HtrA2/XIAP/PARP signaling pathway.

Apoptosis and its therapeutic implications in neurodegenerative diseases

“…The amyloid precursor protein may be translocated to the outer mitochondrial membrane, where it is cleaved by γ-secretase complexes that contain presenilin 1 to form β-amyloid (Guo et al, 2013). Presenilin 1 augments the proteolytic activity of high temperature requirement protein A2 (HTRA2) (Guo et al, 2013), which is then translocated to the cytosol, where it causes degradation of IAPs (Zheng et al, 2021).…”

Mitochondrial quality control proteases and their modulation for cancer therapy

“…Based on the inhibitory effect on HTRA2, UCF-101 prevents the cell from entering apoptosis and further possesses excellent effects against injury in a variety of models. 176 Specifically, UCF-101 alleviates acute lung injury by decreasing inflammatory response, oxidative stress, and apoptosis and may be a candidate for pneumonia treatment. 177 Furthermore, inhibition of the HTRA2/XIAP/PARP signaling pathway reduced cardiomyocyte injury.…”

“…177 Furthermore, inhibition of the HTRA2/XIAP/PARP signaling pathway reduced cardiomyocyte injury. 176 In addition, UCF-101 shows protective effects against nerve injury, cerebral ischemia/reperfusion injury, traumatic spinal cord injury, kidney injury, and intestinal ischemia/ reperfusion injury by modulating oxidative stress and apoptosis. [178][179][180][181] Additionally, UCF-101 alleviated various responses resulting from sepsis, including oxidative brain damage and cognitive impairment in rats.…”

Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review

“…Interestingly, the amyloid precursor protein (APP) might be translocated to the outer mitochondrial membrane, wherein APP can be cleaved via γ-secretase complexes that include PS-1 to generate Aβ [ 123 ]. In addition, PS-1 can induce the proteolytic function of high-temperature requirement protein A2 (HTRA2) [ 123 ], then it can translocate to the cytosol, where it can cause the degradation of apoptotic proteins’ inhibitors [ 124 ]. Apoptosis may be associated with AD pathogenesis, however the proof regarding its effect on neuronal death in the case of AD is limited [ 53 , 125 ].…”