Abstract
The cardioprotective lipoprotein HDL (high-density lipoprotein) prevents myocardial infarction and cardiomyocyte death due to ischemia/reperfusion injury. The scavenger receptor class B, type 1 (SR-B1) is a high-affinity HDL receptor and has been shown to mediate HDL-dependent lipid transport as well as signaling in a variety of different cell types. The contribution of SR-B1 in cardiomyocytes to the protective effects of HDL on cardiomyocyte survival following ischemia has not yet been studied. Here, we use a model of simulated ischemia (oxygen and glucose deprivation, OGD) to assess the mechanistic involvement of SR-B1, PI3K (phosphatidylinositol-3-kinase), and AKT in HDL-mediated protection of cardiomyocytes from cell death. Neonatal mouse cardiomyocytes and immortalized human ventricular cardiomyocytes, subjected to OGD for 4 h, underwent substantial cell death due to necrosis but not necroptosis or apoptosis. Pretreatment of cells with HDL, but not low-density lipoprotein, protected them against OGD-induced necrosis. HDL-mediated protection was lost in cardiomyocytes from SR-B1−/− mice or when SR-B1 was knocked down in human immortalized ventricular cardiomyocytes. HDL treatment induced the phosphorylation of AKT in cardiomyocytes in an SR-B1-dependent manner. Finally, chemical inhibition of PI3K or AKT or silencing of either AKT1 or AKT2 gene expression abolished HDL-mediated protection against OGD-induced necrosis of cardiomyocytes. These results are the first to identify a role of SR-B1 in mediating the protective effects of HDL against necrosis in cardiomyocytes, and to identify AKT activation downstream of SR-B1 in cardiomyocytes.
Highlights
Cardiovascular disease is a leading cause of death and a major burden to the healthcare systems of developed societies [1]
Cells subjected to oxygen and glucose deprivation (OGD) exhibited only very low levels of apoptosis, as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) or annexin V (AxV) staining, and these very low levels were unaffected by high-density lipoprotein (HDL) treatment (Figure 1B–D)
We sought to determine if HDL could protect cardiomyocytes against cell death induced by OGD as a model of induced ischemia and to evaluate if SR-B1, PI3K, and AKT are involved in the protective signaling elicited by HDL
Summary
Cardiovascular disease is a leading cause of death and a major burden to the healthcare systems of developed societies [1]. Low plasma HDL (high-density lipoprotein) cholesterol is associated with increased risk of mortality in patients recovering from myocardial infarction [2], and HDL cholesterol levels are inversely correlated with cardiovascular disease risk [3]. The clinical data are supported by ex vivo experimental evidence, where administration of HDL provides protection against ischemia–reperfusion injury in rodent hearts [4,5], and in vivo experimental evidence demonstrates that overexpression of apolipoprotein (apo) A1 (the major protein component of HDL) protects low-density lipoprotein (LDL) receptor (LDLR−/−) knockout mice from coronary artery ligation-induced myocardial infarction, cardiac dysfunction, and death [6]. ApoA1-deficiency, and a resultant reduction in HDL, impairs cardiomyocyte mitochondrial function and results in larger infarctions following coronary ligation in mice [7]
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