Wei-Wei Lu1, Li-Xin Jia1, Xian-Qiang Ni1, Lei Zhao1, Jin-Rui Chang1, Jin-Sheng Zhang1, Yue-Long Hou1, Yi Zhu1, You-Fei Guan1, Yan-Rong Yu1, Jie Du1, Chao-Shu Tang1, Yong-Fen Qi2. 1. From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.). 2. From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.). yongfenqi@163.com.
Abstract
OBJECTIVE: Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress. APPROACH AND RESULTS: In angiotensin II-induced ApoE-/- mouse and CaCl2-induced C57BL/6J mouse model of AAA, IMD1-53 significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD1-53 significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl2. Mechanistically, IMD1-53 attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD1-53 inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD1-53. In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD17-47 and protein kinase A inhibitor H89 inhibited the effect of IMD1-53, reducing Nox4 protein levels. CONCLUSIONS: IMD1-53 could have a protective effect on AAA by inhibiting oxidative stress.
OBJECTIVE: Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress. APPROACH AND RESULTS: In angiotensin II-induced ApoE-/- mouse and CaCl2-induced C57BL/6J mouse model of AAA, IMD1-53 significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD1-53 significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl2. Mechanistically, IMD1-53 attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD1-53 inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAAmice. Expression of Nox4 was upregulated in humanAAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD1-53. In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD17-47 and protein kinase A inhibitor H89 inhibited the effect of IMD1-53, reducing Nox4 protein levels. CONCLUSIONS: IMD1-53 could have a protective effect on AAA by inhibiting oxidative stress.
Authors: V Šćepanović; G Tasić; N Repac; I Nikolić; A Janićijević; D Todorović; M Stojanović; R Šćepanović; D Mitrović; T Šćepanović; S Borozan; Lj Šćepanović Journal: Mol Biol Rep Date: 2018-09-20 Impact factor: 2.316
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Chia-Hua Wu; Shayan Mohammadmoradi; Jeff Z Chen; Hisashi Sawada; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2018-07 Impact factor: 8.311