Weimin Yu1, Li Xiao1, Yumei Que1, Siqi Li1, Lili Chen2, Pingping Hu1, Rui Xiong3, Francesca Seta4, Hao Chen3, Xiaoyong Tong5. 1. School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China. 2. Wuhan EasyDiagnosis Biomedicine Co., Ltd., Wuhan 430075, China. 3. Chongqing General Hospital, University of Chinese Academy of Science, Chongqing 400013, China. 4. Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. 5. School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China. Electronic address: xiaoyongtong@cqu.edu.cn.
Abstract
BACKGROUND AND AIMS: Angiotensin II (Ang II) is commonly used to induce aortic aneurysm and atherosclerosis in animal models. Ang II upregulates NADPH oxidase isoform Nox4 in aortic smooth muscle cells (SMCs) in mice. However, whether smooth muscle Nox4 is directly involved in Ang II-induced aortic aneurysm and atherosclerosis is unclear. METHODS & RESULTS: To address this, we used smooth muscle-specific Nox4 dominant-negative (SDN) transgenic mice, in which Nox4 activity is constitutively inhibited. In non-transgenic (NTg) mice, Ang II increased the expression of proteins known to contribute to both aortic aneurysm and atherosclerosis, namely osteopontin (OPN), collagen type I&III (Col I&III), matrix metalloproteinase 2 (MMP2), and vascular cell adhesion molecule 1 (VCAM1), which were all significantly downregulated in SDN mice. The number and size of Ang II-induced aorta collateral aneurysms and atherosclerotic lesions in the renal artery and aortic root of SDN mice were significantly decreased compared to NTg mice, and directly correlated with a decrease in OPN expression. Replenishing OPN in SDN SMCs, increased the expression of Col I&III, MMP2, and VCAM1, and promoted SMC proliferation, migration, and inflammation. CONCLUSIONS: Our data demonstrate that smooth muscle Nox4 directly promotes the development of Ang II-induced aortic aneurysm and atherosclerosis, at least in part, through regulating OPN expression.
BACKGROUND AND AIMS: Angiotensin II (Ang II) is commonly used to induce aortic aneurysm and atherosclerosis in animal models. Ang II upregulates NADPH oxidase isoform Nox4 in aortic smooth muscle cells (SMCs) in mice. However, whether smooth muscle Nox4 is directly involved in Ang II-induced aortic aneurysm and atherosclerosis is unclear. METHODS & RESULTS: To address this, we used smooth muscle-specific Nox4 dominant-negative (SDN) transgenic mice, in which Nox4 activity is constitutively inhibited. In non-transgenic (NTg) mice, Ang II increased the expression of proteins known to contribute to both aortic aneurysm and atherosclerosis, namely osteopontin (OPN), collagen type I&III (Col I&III), matrix metalloproteinase 2 (MMP2), and vascular cell adhesion molecule 1 (VCAM1), which were all significantly downregulated in SDNmice. The number and size of Ang II-induced aorta collateral aneurysms and atherosclerotic lesions in the renal artery and aortic root of SDNmice were significantly decreased compared to NTgmice, and directly correlated with a decrease in OPN expression. Replenishing OPN in SDN SMCs, increased the expression of Col I&III, MMP2, and VCAM1, and promoted SMC proliferation, migration, and inflammation. CONCLUSIONS: Our data demonstrate that smooth muscle Nox4 directly promotes the development of Ang II-induced aortic aneurysm and atherosclerosis, at least in part, through regulating OPN expression.
Authors: Haocheng Lu; Wa Du; Lu Ren; Milton H Hamblin; Richard C Becker; Y Eugene Chen; Yanbo Fan Journal: J Am Heart Assoc Date: 2021-11-19 Impact factor: 6.106