Novel Mouse Model of Coronary Atherosclerosis With Myocardial Infarction: Insights Into Human CAD.

Abstract

Background: Coronary artery disease is a chronic and multifactorial disease with acute manifestations. Little is known about the concomitant impact of hypercholesterolemia and hypertension on the development of coronary atherosclerosis.

Methods: ApoE and scavenger receptor B1, genes both associated with human hypercholesterolemia, were inactivated in mice by inserting a scavenger receptor B1 knockdown cassette downstream of the ApoE promoter. Meanwhile, a doxycycline-inducible Ang II (angiotensin II) expression cassette was introduced. The resultant mutant mice (ApoE^SA/SA), isolated arteries, and pharmacological/genetic interventions were employed to assess the impacts of hypercholesterolemia and hypertension on coronary atherosclerosis and mechanisms.

Results: ApoE^SA/SA mice developed mild coronary atherosclerosis with heart failure after chronic feeding with western diet. Strikingly, additional Ang II-induced hypertension, but not norepinephrine-induced hypertension, drastically accelerated coronary atherogenesis, exhibiting endothelial erosion, myeloid cell infiltration, spontaneous plaque rupture, and myocardial infarction, which was Ang II type 1 receptor-dependent. In contrast to this severe coronary atherosclerosis, femoral arteries were resistant to atherogenesis. Proteomic profiling revealed substantial differences in vasomotor reactivity and inflammation. Endothelium-dependent dilatation of coronary arteries was highly susceptible to the combination of hypercholesterolemia and hypertension compared with femoral arteries, and a similar vulnerability was also observed in human coronary arteries. Ex vivo exposure to Ang II markedly impaired endothelium-dependent dilatation in coronary arteries, but not in femoral arteries. Consistent with its less coronary atherogenic activity, norepinephrine dilated coronary arteries while constricting femoral arteries. Furthermore, dilatation of the coronary artery was more dependent on prostaglandins than that in femoral artery. Coronary prostaglandin biosynthesis was suppressed during atherogenesis and, conversely, an elevated coronary production of prostaglandins after methotrexate administration was associated with improved endothelial function and better cardiovascular survival.

Conclusions: The combination of hypercholesterolemia and Ang II-induced hypertension exerts strong synergistic effects on coronary atherogenesis. This is attributable to a selective vulnerability of coronary endothelium-dependent vasodilator responses to Ang II exposure and prostaglandin inhibition. ApoE^SA/SA represents a novel and convenient mouse model of coronary atherosclerosis with spontaneous myocardial infarction.