PMID- 32060588 OWN - NLM STAT- MEDLINE DCOM- 20210614 LR - 20210614 IS - 1432-1440 (Electronic) IS - 0946-2716 (Linking) VI - 98 IP - 4 DP - 2020 Apr TI - AVE0991, a nonpeptide angiotensin-(1-7) mimic, inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E knockout mice. PG - 541-551 LID - 10.1007/s00109-020-01880-4 [doi] AB - AVE0991, a nonpeptide angiotensin-(1-7) mimic, has similar protective effects for cardiovascular system to Ang-(1-7). In this article, we aimed to explore the effects of AVE0991 and Ang-(1-7) on abdominal aortic aneurysm (AAA) induced by Ang II in apolipoprotein E knockout mice. The mice AAA model was established by Ang II infusion, and then mice received different treatment with saline, Ang II (1.44 mg/kg/day), different dose AVE0991 (0.58 or 1.16 mumol/kg/day), or Ang-(1-7) (400 ng/kg/min). The incidence of AAA was 76%, 48%, 28%, and 24% in the vehicle, the low-dose AVE0991, high-dose AVE0991, and the Ang-(1-7) group, respectively. In comparison with control group, AVE0991 and Ang-(1-7) treatment significantly increased smooth muscle cells and decreased macrophage accumulation, the expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-alpha), and the expression and activity of metalloproteinases 2 and 9 in mice AAA model or in human smooth muscle cells (hVSMCs). The therapeutic effects may be contributed to reduction of oxidative stress and downregulation of P38 and ERK1/2 signal pathways via Mas receptor activation, whereas the positive impacts were reversed by co-administration with the Mas antagonist A779 (400 ng/kg/min) and AVE0991 in Ang II-infused mice or in hVSMCs. Therefore, AVE0991 and Ang-(1-7) might be novel and promising interventions in the prevention and treatment of AAA. KEY MESSAGES: * AVE0991 dose-dependently inhibited Ang II-induced AAA formation in Apoe(-/-) mice. * Ang-(1-7) played the same protective role as high-dose AVE0991. * Inhibition of Mas receptor with A779 could reverse the protective effect of AVE0991. * The therapeutic effects may be contributed to reduction of oxidative stress and downregulation of P38 and ERK1/2 signal pathways via Mas receptor activation. FAU - Ma, Hui AU - Ma H AD - Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. FAU - Wang, Yu-Lin AU - Wang YL AD - Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. FAU - Hei, Nai-Hao AU - Hei NH AD - Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. FAU - Li, Jun-Long AU - Li JL AD - Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. FAU - Cao, Xin-Ran AU - Cao XR AD - Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. FAU - Dong, Bo AU - Dong B AD - Department of Pediatrics and Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. bodong@sdu.edu.cn. FAU - Yan, Wen-Jiang AU - Yan WJ AUID- ORCID: 0000-0003-4032-7983 AD - The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China. ywj1987606@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200214 PL - Germany TA - J Mol Med (Berl) JT - Journal of molecular medicine (Berlin, Germany) JID - 9504370 RN - 0 (AVE 0991) RN - 0 (Apolipoproteins E) RN - 0 (Imidazoles) RN - 0 (Lipids) RN - 0 (Peptide Fragments) RN - 11128-99-7 (Angiotensin II) RN - 9041-90-1 (Angiotensin I) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - IJ3FUK8MOF (angiotensin I (1-7)) SB - IM EIN - J Mol Med (Berl). 2020 Mar 30;:. PMID: 32232510 MH - Angiotensin I/chemistry/*pharmacology MH - Angiotensin II/*adverse effects MH - Animals MH - Aortic Aneurysm, Abdominal/drug therapy/*etiology/pathology/prevention & control MH - Apolipoproteins E/*deficiency MH - Blood Pressure MH - Disease Models, Animal MH - Humans MH - Imidazoles/chemistry/*pharmacology MH - Immunohistochemistry MH - Lipids/blood MH - MAP Kinase Signaling System/drug effects MH - Male MH - Matrix Metalloproteinase 2/genetics/metabolism MH - Matrix Metalloproteinase 9/genetics/metabolism MH - Mice MH - Mice, Knockout MH - *Molecular Mimicry MH - Myocytes, Smooth Muscle/drug effects/metabolism MH - Oxidative Stress/drug effects MH - Peptide Fragments/chemistry/*pharmacology MH - p38 Mitogen-Activated Protein Kinases/metabolism OTO - NOTNLM OT - AVE0991 OT - Abdominal aortic aneurysm OT - Angiotensin-(1-7) OT - Inflammation OT - Mas receptor OT - Matrix metalloproteinase EDAT- 2020/02/16 06:00 MHDA- 2021/06/16 06:00 CRDT- 2020/02/16 06:00 PHST- 2019/11/26 00:00 [received] PHST- 2020/01/16 00:00 [accepted] PHST- 2020/01/14 00:00 [revised] PHST- 2020/02/16 06:00 [pubmed] PHST- 2021/06/16 06:00 [medline] PHST- 2020/02/16 06:00 [entrez] AID - 10.1007/s00109-020-01880-4 [pii] AID - 10.1007/s00109-020-01880-4 [doi] PST - ppublish SO - J Mol Med (Berl). 2020 Apr;98(4):541-551. doi: 10.1007/s00109-020-01880-4. Epub 2020 Feb 14.