Natriuretic peptides protect against apoptosis and increase cGMP around cardiomyocyte mitochondria

Abstract

AbstractNatriuretic peptides (NPs) increase cGMP, show beneficial cardiovascular effects and has been shown to regulate energy metabolism in other tissues. However, little is known about their direct effect on cardiac mitochondria and cardiomyocyte apoptosis. Here, we examined whether NPs increase cGMP around mitochondria and alter apoptosis in cardiomyocytes. Stimulating with ANP or CNP reduced apoptosis, together with reduced caspase 9 activation and cytochrome c release, suggesting that NPs decrease apoptosis through the intrinsic pathway that involves mitochondria. We engineered a novel FRET-based biosensor with high selectivity towards cGMP and targeted this to the outer mitochondrial membrane (OMM) and found that ANP and CNP increase cGMP at the OMM. Moreover, ANP and CNP increased phosphorylation of the pro-apoptotic protein Drp1 and CNP prevented fragmentation of mitochondria. We suggest that cGMP increase in the OMM microdomain inhibits the proapoptotic protein Drp1, leading to reduced mitochondrial fragmentation that inhibits apoptosis.