Abstract 100: Smooth Muscle Cell-Specific Deficiency of ACE Attenuates AngI-Induced Ascending Aortic Dilation in Male LDL Receptor -/- Mice

Abstract

Introduction and Objectives: Angiotensin II (AngII) infusion into hypercholesterolemic mice induces atherosclerosis and luminal dilations in both ascending and abdominal aortic regions. Angiotensin-converting enzyme (ACE) is the major enzyme converting AngI to AngII. We demonstrated previously that AngI induced atherosclerosis and aortic aneurysms through an ACE-dependent mechanism. ACE is abundant in smooth muscle cells (SMCs), the major cell type of the aortic wall. The purpose of this study was to determine whether SMC-derived ACE contributes to AngI-induced aortic pathologies. Methods and Results: ACE floxed mice were bred into an LDL receptor -/- background. Subsequently, female mice were bred to male Cre transgenic mice with a SM22 promoter to generate wild type (smACE+/+) and SMC-specific ACE deficient (smACE-/-) mice. SMC-specific deficiency of ACE did not affect serum ACE activity, but ablated ACE protein abundance and activity in the aortic media. smACE+/+ (male n=24 male and female n=7) or smACE-/- mice (male n=33 and female n=7) were infused with AngI (1 μg/kg/min) for 4 weeks through osmotic minipumps. Mice were fed a western diet for 1 week prior to pump implantation and during 4 weeks of AngI infusion. Atherosclerosis was quantified on intimal surfaces of aortas by an en face technique. Maximal ex vivo diameters of suprarenal aortas and intimal area of ascending aortas were measured to compare abdominal and ascending aortic dilation, respectively. SMC-specific deficiency of ACE had no effect on percent atherosclerotic lesion area in aortic arches. There was no significant difference of abdominal aortic dilation between smACE+/+ and -/- mice. In contrast, ACE deficiency in SMCs significantly attenuated dilation of ascending aortas in male (smACE+/+ versus -/- mice: 12.2 ± 0.2 versus 10.7 ± 0.4 mm2, P=0.04) but not in female mice (smACE +/+ versus -/- 8.2 ± 0.3 versus 8.7 ± 0.5 mm 2 ; P=0.4). Conclusion: SMC-specific deficiency of ACE attenuates AngI-induced ascending aortic dilation in male LDL receptor -/- mice, but had no effect on abdominal aortic aneurysms and atherosclerosis.