Improving heart function by modulating myocardiocyte autophagy: a possible novel mechanism for cardiovascular protection of high-density lipoprotein

Abstract

BackgroundHigh-density lipoprotein (HDL) has been shown to confer cardiovascular protection in clinical and epidemiologic studies. Emerging evidence suggests that many of the cardioprotective functions of HDL may be due to the phospholipid sphingosine-1-phosphate (S1P).Presentation of the hypothesisHDL-S1P binds to S1P receptors in the heart, activating PI3K/Akt signaling and myocyte survival. PI3K/Akt is a classic signaling modulator of autophagy. Excessive autophagy due to cell death and cardiomyocyte loss may contribute to impaired heart function during pressure overload-induced heart failure. Therefore, we hypothesize that HDL-S1P may suppress excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling. Further, reconstituted HDL (including S1P) may protect heart function during pressure overload-induced heart failure.Testing the hypothesisWe will design the following experiments to test this hypothesis. (1) We will treat cells and mice with PI-3 kinase inhibitors to examine if HDL-S1P downregulates expression of Autophagy-related genes (ATGs) and proteins via activation of PI3K/Akt signaling. (2) We will use siRNA against S1P receptors or inhibitors of S1P receptors to determine which types of S1P receptors participate in this mechanism. (3) We will also examine if reconstituted HDL (including S1P) improves heart function during pressure overload-induced heart failure by suppressing excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling.Implications of the hypothesisUnderstanding the autophagy signaling pathway modulated by HDL-S1P will make a major contribution to the field by identifying a novel mechanism for cardiovascular protection of high-density lipoprotein. Further, using reconstituted HDL to improve heart function would provide a novel therapeutic approach for pressure overload–induced heart failure.

Danshensu alleviates cardiac ischaemia/reperfusion injury by inhibiting autophagy and apoptosis via activation of mTOR signalling

“…We found that mTOR activity was suppressed in response to I/R, which was a crucial step for autophagic cell death in cardiomyocytes. Although autophagy is thought to play a central role in regulating cell death and survival, our data suggest that excessive autophagy, such as increased formation of autophagosomes and autophagic flux can lead to cardiomyocyte cell death . Despite our finding that DSS activation of mTOR can reduce ischaemia‐induced autophagy and tissue injury, it remains unclear whether continuous mTOR activation acts as an endogenous survival signalling mechanism.…”

Cardiac ubiquitin ligases: Their role in cardiac metabolism, autophagy, cardioprotection and therapeutic potential

“…In the context of high-fat diet induced accumulation of lipids, the proper autophagic clearance has proven important in attenuating reactive oxygen species 25–27 . The attenuation of the lipotoxic cardiomyopathy in pressure overload-induced heart failure 28 similarly demonstrates the importance of autophagy in clearing lipids in cardiac stress, a process regulated by oxidized phospholipids 29 .…”

Genetic Variants and Functional Analyses of the ATG16L1 Gene Promoter in Acute Myocardial Infarction

“…Pompe’s disease, caused by a deficiency of glycogenic glycemic enzyme acid α-glucosidase, results from the accumulation of autophagosomes ( Fukuda et al, 2006 ). Previous studies have demonstrated that the expression of ATG16L1 in atherosclerosis is closely related to the instability of lesions on atherosclerotic plaques ( Wang and Ye, 2014 ). In the necrotic core and surrounding area of human atherosclerotic plaque, particularly the shoulder area, ATG16L1 protein is abundantly expressed, and ATG16L1 immunomarkers are mainly found in the plaque endothelial cells and foamy smooth muscle cells.…”