Feng Zhang1, Sufang Li2, Junxian Song2, Jun Liu2, Yuxia Cui2, Hong Chen3. 1. Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 2. Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. 3. Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. Electronic address: chenhongbj@medmail.com.cn.
Abstract
BACKGROUND AND AIMS: Angiotensin II (Ang II) is a bioactive peptide that is related to cardiovascular disease such as atherosclerosis, whereas angiotensin-(1-7) (Ang-(1-7)) is a counter-regulator of angiotensin II, which protects against cardiovascular disease. Matrix metalloproteinase 8 (MMP-8) is thought to participate in plaque destabilization though degradation of extracellular matrix, improving the development of atherosclerosis. Whether Ang-(1-7) modulates Ang II-induced MMP-8 remains unclear. In this study, we investigated the effect of Ang-(1-7) on Ang II-induced MMP-8 expression in smooth muscle cells. METHODS: Smooth muscle cells were treated with Ang II, Ang-(1-7) and their antagonists. In addition, ApoE knockout mice were fed a high fat diet and subcutaneously injected with Ang II, Ang-(1-7), Ang II+Ang-(1-7) (±A779). RESULTS: We found that Ang II increased MMP-8 mRNA and protein expression in vascular smooth muscle cells, while Ang-(1-7) alone had no effect. However, Ang-(1-7) inhibited Ang II-induced MMP-8 expression. The inhibitory effect of Ang-(1-7) could be abolished by the competitive antagonist of Ang-(1-7) at the MAS receptor. Furthermore, Ang II induced p38 MAPK activation, and this was inhibited by the treatment of Ang-(1-7). Ang II-induced MMP-8 expression could be attenuated by the p38 MAPK inhibitor SB203580. Ang-(1-7) also significantly suppressed Ang II-induced MMP-8 in both atherosclerotic plaques and serum in ApoE-/- mice. The atherosclerotic plaques in mice treated with Ang-(1-7) and Ang II appeared to be more stable with more type I collagen contents than those in mice treated with Ang II. CONCLUSIONS: Our results suggest that Ang-(1-7) plays an important role in protecting against atherosclerosis via counter-regulation of Ang II-induced MMP-8.
BACKGROUND AND AIMS: Angiotensin II (Ang II) is a bioactive peptide that is related to cardiovascular disease such as atherosclerosis, whereas angiotensin-(1-7) (Ang-(1-7)) is a counter-regulator of angiotensin II, which protects against cardiovascular disease. Matrix metalloproteinase 8 (MMP-8) is thought to participate in plaque destabilization though degradation of extracellular matrix, improving the development of atherosclerosis. Whether Ang-(1-7) modulates Ang II-induced MMP-8 remains unclear. In this study, we investigated the effect of Ang-(1-7) on Ang II-induced MMP-8 expression in smooth muscle cells. METHODS: Smooth muscle cells were treated with Ang II, Ang-(1-7) and their antagonists. In addition, ApoE knockout mice were fed a high fat diet and subcutaneously injected with Ang II, Ang-(1-7), Ang II+Ang-(1-7) (±A779). RESULTS: We found that Ang II increased MMP-8 mRNA and protein expression in vascular smooth muscle cells, while Ang-(1-7) alone had no effect. However, Ang-(1-7) inhibited Ang II-induced MMP-8 expression. The inhibitory effect of Ang-(1-7) could be abolished by the competitive antagonist of Ang-(1-7) at the MAS receptor. Furthermore, Ang II induced p38 MAPK activation, and this was inhibited by the treatment of Ang-(1-7). Ang II-induced MMP-8 expression could be attenuated by the p38 MAPK inhibitor SB203580. Ang-(1-7) also significantly suppressed Ang II-induced MMP-8 in both atherosclerotic plaques and serum in ApoE-/- mice. The atherosclerotic plaques in mice treated with Ang-(1-7) and Ang II appeared to be more stable with more type I collagen contents than those in mice treated with Ang II. CONCLUSIONS: Our results suggest that Ang-(1-7) plays an important role in protecting against atherosclerosis via counter-regulation of Ang II-induced MMP-8.
Authors: Fernando Pedro de Souza-Neto; Melissa Carvalho Santuchi; Mario de Morais E Silva; Maria José Campagnole-Santos; Rafaela Fernandes da Silva Journal: Curr Hypertens Rep Date: 2018-03-14 Impact factor: 5.369