Abstract 3133: Selective Vulnerability Of Coronary Arteries To Hypercholesterolemia And Angiotensin II-induced Hypertension

Abstract

Hypercholesterolemia and hypertension are major risk factors for cardiovascular disease. We aimed to determine their concomitant effects on coronary atherogenesis. An SR-BI (an HDL receptor) suppression and doxycycline-inducible angiotensin II (AngII) cassette was inserted downstream of the ApoE promoter to ablate ApoE expression and overproduce AngII. The resulting mutants (ApoE SA/SA ) exhibited mild coronary atherosclerosis after Western diet feeding. Doxycycline induced AngII-induced hypertension and drastically accelerated coronary atherosclerosis, with lesions exhibiting endothelial erosion, myeloid cell infiltration, and plaque rupture, resulting in myocardial infarction, heart failure, and male-propensity of sudden death. AngII, but not norepinephrine-induced hypertension, led to severe coronary atherogenesis under hypercholesterolemia, which was abolished by losartan. Notably, norepinephrine constricted femoral arteries, but it dilated coronary arteries. In contrast to coronary arteries, femoral arteries did not develop atherosclerosis. Proteomic analyses revealed distinctive differences between the two vascular beds. Coronary vasodilation to acetylcholine was highly susceptible to the risk factors, compared to femoral artery, and was markedly attenuated by AngII exposure and prostaglandin inhibition. Interestingly, coronary prostaglandin synthesis was suppressed in atherogenesis, and elevated coronary capacity to produce prostaglandins following methotrexate administration was associated with ameliorated early coronary endothelial dysfunction and improved cardiovascular survival, featuring markedly reduced lesional myeloid cells. Coronary arteries from patients with hypertension and hypercholesterolemia showed substantially impaired endothelium-dependent vasodilation, compared to internal mammary arteries of similar risk exposure, whereas their endothelium-independent vasodilation was intact. Thus, the combination of hypercholesterolemia and AngII-induced hypertension drastically promoted coronary atherosclerosis with spontaneous lesion rupture, which confers a selective vulnerability of coronary vasodilation to prostaglandin inhibition and AngII exposure.