Inhibition of mitochondrial activity ameliorates atherosclerosis in ApoE-/- mice via suppressing vascular smooth cell activation and macrophage foam cell formation.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Weiwei Xia, Yuanyuan Li, Mengying Wu, Jie Yin, Yue Zhang, Hongbing Chen, Songming Huang, Zhanjun Jia, Aihua Zhang
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 120 Issue 10 Pg. 17767-17778 (10 2019) ISSN: 1097-4644 [Electronic] United States
• PMID: 31131474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Apolipoproteins E
• CD36 Antigens
• Lipids
• Lipoproteins, LDL
• Pyrimidines
• Strobilurins
• oxidized low density lipoprotein
• Rotenone
• Proto-Oncogene Proteins c-akt
• Electron Transport Complex I
• Electron Transport Complex III
• azoxystrobin

Topics

• Animals
• Apolipoproteins E (deficiency, metabolism)
• Atherosclerosis (metabolism, pathology)
• CD36 Antigens (metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Electron Transport Complex I (antagonists & inhibitors, metabolism)
• Electron Transport Complex III (antagonists & inhibitors, metabolism)
• Foam Cells (drug effects, metabolism)
• Lipids (chemistry)
• Lipoproteins, LDL (pharmacology)
• Male
• Mice, Knockout
• Mitochondria (drug effects, metabolism)
• Muscle, Smooth, Vascular (pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology)
• Rotenone (toxicity)
• Strobilurins (pharmacology)