azoxystrobin and Atherosclerosis

Atherosclerosis involves disorders in lipoprotein metabolism and inflammation. Mitochondrial dysfunction plays a critical role in promoting cell apoptosis, inflammation, and oxidative stress involved in the progress of atherosclerosis. Whereas the direct effect of mitochondrial activity modulation on atherogenesis remains unclear. This study evaluated the effect of a mitochondrial complex inhibitor on atherosclerosis in ApoE-deficient mice as well as the potential mechanisms.. We treated ApoE-deficient mice with mitochondrial complex I inhibitor rotenone in the western diet and found that rotenone attenuated early and advanced atherosclerosis with no effect on serum lipoprotein levels. Mechanistic investigation showed that rotenone suppressed primary macrophage foam cell formation possibly by suppressing CD36. In addition, we also found that the inhibitory effect of rotenone on VSMC proliferation and migration possibly by targeting the PI3K/AKT signaling. Consistently, mitochondrial complex III inhibitor azoxystrobin also exhibited similar actions as rotenone in VSMCs but not in macrophages.. Inhibition of mitochondrial activity could significantly attenuate atherosclerosis possibly by modulating CD36-mediated macrophage foam cell formation and PI3K/AKT signaling pathway-associated VSMC activation. Targeting mitochondrial activity might be the potential therapeutic strategy for atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; CD36 Antigens; Cell Movement; Cell Proliferation; Electron Transport Complex I; Electron Transport Complex III; Foam Cells; Lipids; Lipoproteins, LDL; Male; Mice, Knockout; Mitochondria; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrimidines; Rotenone; Strobilurins