Abstract 18250: Deficiency of Angiotensin-converting Enzyme in Vascular Smooth Muscle Cells Reduces Hypercholesterolemia-induced Atherosclerosis
Background and Objective: Angiotensin-converting enzyme (ACE) is the major enzyme that converts AngI to AngII. There is compelling evidence that inhibition of ACE reduces atherosclerosis in several animal models. Although leukocyte infiltration is pronounced in atherosclerotic lesions, we demonstrated recently that leukocyte ACE had only a modest effect on atherosclerosis development. ACE is abundant in smooth muscle cells (SMCs), the major cell type of the aortic wall. In this study, we determined whether SMC-derived ACE contributes to hypercholesterolemia-induced atherosclerosis.
Methods and Results: Immunostaining of normal aorta demonstrated that ACE protein was abundant in medial SMCs. Using adventitia-free and endothelium-denuded aortas from C57BL/6 mice, the presence of the enzyme was confirmed by real time PCR determination of ACE mRNA abundance, Western blotting of protein, and fluorimetric analyses of enzyme activity. To determine whether SMC-specific deficiency of ACE reduces atherosclerosis, we developed ACE floxed mice expressing Cre under the control of the SM22 promoter (SM22-Cre 0/0 versus SM22-Cre +/0) in an LDL receptor -/- background. SMC-specific deficiency of ACE was confirmed by lack of the ACE protein and activity in adventitia-free and endothelium-denuded aortas. Both male and female mice with SMC-specific deficiency of ACE and the littermate wild type controls were fed a saturated fat-enriched diet (Harlan Teklad; Diet # TD.88137) for 12 weeks. Systolic blood pressure, as measured using a tail-cuff system, was not different between the two groups. There were also no differences on body weight and plasma cholesterol concentrations between the two groups. Atherosclerosis was assessed on the intima surface of aortic arches by en face analyses. SMC-specific deficiency of ACE led to reduced lesion sizes in both male and female (SM-22 Cre 0/0 versus Cre +/0: 19.3 ± 2.2 % versus 9.9 ± 1.9 %, P=0.005 in male; and 22.3 ± 2.7 % versus 14.7 ± 1.2 %, P=0.02).
Conclusion: ACE in SMCs contributes to hypercholesterolemia-induced atherosclerosis in mice.
Author Disclosures: X. Chen: None. D.A. Howatt: None. A. Balakrishnan: None. J.J. Moorleghen: None. L.A. Cassis: None. A. Daugherty: None. H. Lu: None.
- © 2014 by American Heart Association, Inc.