Abstract 1195: Acceleration of Hyperlipidemia-induced Atherosclerosis in Apolipoprotein E and Angiotensin-converting Enzyme 2 Double-Knockout Mice
Background: Angiotensin-converting enzyme 2 (ACE2) is a homologue of ACE, and hydrolyzes angiotensin II (Ang II) as a negative regulator of the renin-angiotensin system. Recent studies have documented its presence in heart, kidney, testis, and other tissues including aorta; however, its role on pathological vascular remodeling of large vessels remains unclear.
Methods and Results: To evaluate a effect of ACE2 in hyperlipidemia-induced atherosclerosis, apolipoprotein E-deficient (ApoE−/−) mice were crossed with ACE2-deficient (ACE2−/y) mice to obtain homozygous double-knockout mice (ApoE−/−-ACE2−/y mice; C57BL/6 background). Male ApoE−/− and ApoE−/−-ACE2−/y mice were fed a Western-type diet for 12 weeks. The diet induced severe atherosclerotic lesion formation in both aortic root stained with oil red O (cross-section method) and the whole aorta stained with Sudan IV (en face method) in ApoE−/− mice. In the age-matched ApoE−/−-ACE2−/y littermates, diet-induced atherosclerotic lesion formation was more markedly augmented. Plaque area in aortic root and percent plaque area to the total luminal surface area in the whole aorta were as follows: 16.8±5.7 μm2×103 and 11.2±2.2% in ApoE−/− mice vs. 23.1±4.0 μm2×103 and 19.4±4.8% in ApoE−/−-ACE2−/y mice (p<0.05, respectively). There were no significant differences in plasma lipid levels and blood pressure between ApoE−/− and ApoE−/−-ACE2−/y mice. The number of macrophages in atherosclerotic plaque, identified by MOMA-2 staining, and quantitative mRNA expression of MMP-9 in the aorta, measured by real-time RT-PCR, were both significantly increased in ApoE−/−-ACE2−/y mice. In addition, the concentration of Ang II in thoracic aorta was higher in ApoE−/−-ACE2−/y mice than in ApoE−/− mice. On the other hand, oral administration with an angiotensin type 1 receptor blocker, olmesartan (1 mg/kg/day), markedly attenuated diet-induced atherosclerosis in ApoE−/−-ACE2−/y mice irrespective of blood pressure and plasma lipid levels.
Conclusions: Genetic disruption of ACE2 leads to acceleration of hyperlipidemia-induced atherosclerosis in ApoE−/− mice, which are assoicated with local accumulation of Ang II in the aorta. These results suggest a potential protective role of ACE2 against atherogenesis.