Disruption of adipocyte HIF-1 α improves atherosclerosis through the inhibition of ceramide generation.

Atherosclerosis is a chronic multifactorial cardiovascular disease. Western diets have been reported to affect atherosclerosis through regulating adipose function. In high cholesterol diet-fed ApoE -/- mice, adipocyte HIF-1 α deficiency or direct inhibition of HIF-1 α by the selective pharmacological HIF-1 α inhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation, which lowers cholesterol levels and reduces inflammatory responses, resulting in improved dyslipidemia and atherogenesis. Smpd3 , the gene encoding neutral sphingomyelinase, is identified as a new target gene directly regulated by HIF-1 α that is involved in ceramide generation. Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1 α -deficient mice. Therefore, HIF-1 α inhibition may constitute a novel approach to slow atherosclerotic progression.