PCSK9 Inhibitor Alirocumab Improves Diabetic Cardiomyopathy Through the ERK/p38 MAPK Signaling Pathway.

PCSK9 is a gene associated with familial hypercholesterolemia and is involved in other biological processes such as apoptosis, autophagy, and inflammatory responses. This study aims to further validate whether PCSK9 inhibitors can improve diabetic cardiomyopathy and elucidate their mechanisms of action. This study utilized H9c2 cells and C57BL/6J mice to validate the efficacy of the PCSK9 inhibitor alirocumab through in vivo and in vitro experiments. In vitro, alirocumab was shown to enhance cell viability and reduce oxidative stress in H9c2 cells under high glucose stress. It can also decrease the expression levels of inflammatory reaction and mitochondrial apoptosis-related proteins. Through in vivo experiments, we demonstrated that alirocumab can reduce myocardial hypertrophy and improve cardiac function in diabetic cardiomyopathy mice. Meanwhile, alirocumab treatment increased mitochondrial size and quantity in the hearts of diabetic cardiomyopathy mice, promoted mitochondrial fusion, and reduced the number of damaged mitochondria. Alirocumab could also reduce the percentage of myocardial fibrosis and oxidative stress in mice. Finally, we found that alirocumab can improve cardiac function in diabetic cardiomyopathy through the ERK/p38 MAPK pathway. Our data demonstrate that the PCSK9 inhibitor alirocumab provides protective effects against diabetic cardiomyopathy, offering fundamental experimental support for its clinical application in this condition.