Deletion of Angiotensin-converting Enzyme 2 Promotes the Development of Atherosclerosis and Arterial Neointima Formation.

Cardiovascular Research

PubMedID: 24193738

Sahara M, Ikutomi M, Morita T, Minami Y, Nakajima T, Hirata Y, Nagai R, Sata M. Deletion of Angiotensin-converting Enzyme 2 Promotes the Development of Atherosclerosis and Arterial Neointima Formation. Cardiovasc Res. 2014;101(2):236-46.
AIMS
Angiotensin-converting enzyme 2 (ACE2) is known as a negative regulator of the renin-angiotensin system. We aimed to determine the roles of ACE2 on the development of vascular diseases.Methods and ResultsUsing two diversely different models of vascular diseases, hyperlipidemia-induced atherosclerosis in apolipoprotein E knockout (KO) mice and mechanical injury-induced arterial neointimal hyperplasia in C57Bl6 mice, we examined whether ACE2 deficiency could affect formation of the vascular lesions. ACE2 deficiency resulted in significantly larger vascular lesions in both aortic atherosclerotic plaques and arterial neointima formation, compared to ACE2(+) control. These ACE2-deficient vascular lesions exhibited enhanced accumulation of macrophages into the lesions and proliferation of vascular smooth muscle cells (VSMCs), accompanied with increased angiotensin II (Ang-II) levels and enhanced expression of vascular inflammation-related genes, including vascular cell adhesion molecule (VCAM)-1, monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)9 in aorta/artery tissues. Primary bone marrow macrophages and aortic VSMCs isolated from ACE2 KO mice also displayed enhanced proinflammatory responsiveness such as upregulated gene/protein expression of VCAM-1, MCP-1 and MMP9 to stimulation with tumor necrosis factor-a and Ang-II. The similar phenotype was shown in human macrophages and aortic VSMCs that were transfected with ACE2-specific siRNA. In ACE2-deficient VSMCs, inhibition of c-Jun N-terminal kinase (JNK) by pharmacological blockade with SP600125 or genetic knockdown with JNK-specific siRNA significantly attenuated their proinflammatory phenotype.

CONCLUSION
ACE2 deficiency promotes the development of vascular diseases associated with Ang-II-mediated vascular inflammation and activation of the JNK signaling, leading to the notion that ACE2 potentially confers protection against vascular diseases.