Abstract 5569: Neointimal Hyperplasia After Mechanical Endovascular Injury is Augmented Through Angiotensin II-mediated Regional Vascular Inflammation via Activation of the JNK Pathway in Angiotensin-converting Enzyme 2-deficient Mice
Background: Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system, although its role on vascular inflammation and atherosclerosis remains unclear.
Methods and Results: Male ACE2-deficient (ACE2−/y) and wild-type (ACE2+/y) mice underwent wire-mediated endovascular injury in femoral artery. After 4 weeks, the injured artery in ACE2−/y mice exhibited marked neointimal hyperplasia compared with that in ACE2+/y mice. The intima/media ratio in the vascular lesion was 1.97±0.31 in ACE2+/y mice and 2.78±0.49 in ACE2−/y mice (P<0.05). There were no significant differences in blood pressure between both mice. In histology, the accumulation of macrophages in lesions was significantly augmented in ACE2−/y mice. ACE2 protein expression in vascular cells in wild-type mice was detected by immunohistochemistry and western blotting, and the concentration of angiotensin II (Ang-II) in the injured artery was higher in ACE2−/y mice than in ACE2+/y mice. In addition, in the injured artery, quantitative mRNA expressions of vascular inflammatory molecules such as VCAM-1, MCP-1, TNFα, and MMP9 were increased more markedly in ACE2−/y mice. In contrast, an ARB, olmesartan, attenuated the lesion formation and mRNA expressions of these molecules in the injured artery in ACE2−/y mice. Next, we analyzed phosphorylation status of ERK and JNK in aortic vascular smooth muscle cells (VSMCs), which were derived from ACE2+/y or ACE2−/y mice and were stimulated with Ang-II. Although Ang-II increased ERK and JNK phosphorylation in VSMCs of both mice, the increase was greater in VSMCs of ACE2−/y mice. Moreover, we evaluated which signaling pathway mediated Ang-II-induced upregulation of VCAM-1 and MMP9 in VSMCs. Although an ERK inhibitor PD98059 had no impact on Ang-II-induced upregulation of VCAM-1 and MMP9 mRNA expressions, a JNK inhibitor SP600125 significantly attenuated them, suggesting the central role of the JNK pathway in transducing the impact of Ang-II on vascular inflammation.
Conclusions: ACE2 deletion induces marked neointimal formation in femoral artery after vascular injury through Ang-II-mediated regional vascular inflammation via activation of the JNK pathway. ACE2 may confer protection against vascular diseases.