In failing hearts, the dominant AMPKα isoform switched from AMPKα2 to AMPKα1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPKα2 was essential for efficient mitophagy to prevent the progression of HF.
CD36, also known as the scavenger receptor B2, is a multifunctional receptor widely expressed in various organs. CD36 plays a crucial role in the uptake of long-chain fatty acids, the main metabolic substrate in myocardial tissue. The maturation and transportation of CD36 is regulated by post-translational modifications, including phosphorylation, ubiquitination, glycosylation, and palmitoylation. CD36 is decreased in pathological cardiac hypertrophy caused by ischemia-reperfusion and pressure overload, and increased in diabetic cardiomyopathy and atherosclerosis. Deficiency of CD36 alleviates diabetic cardiomyopathy and atherosclerosis, while overexpression of CD36 eliminates ischemia-reperfusion damage, together suggesting that CD36 is closely associated with the progression of cardiovascular diseases and may be a new therapeutic target. This review summarizes the regulation and post-translational modifications of CD36 and evaluates its role in cardiovascular diseases and its potential as a therapeutic target.
Background
Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca
2+ overload. In this study, we investigated the effects of ranolazine on pressure overload‐induced cardiac hypertrophy and heart failure in mice.
Methods and Results
Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca
2+ release and increased SR Ca
2+ leak. Ranolazine restored aberrant SR Ca
2+ handling induced by pressure overload. Ranolazine also suppressed Na
+ overload induced in the failing heart, and restored Na
+‐induced Ca
2+ overload in an sodium‐calcium exchanger (NCX)‐dependent manner. Ranolazine suppressed the Ca
2+‐dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor‐2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T‐cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER‐initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER‐initiated cardiomyocyte apoptosis.
Conclusions
Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload‐induced cardiac hypertrophy and systolic and diastolic function by restoring Na+ and Ca
2+ handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.
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