PMID- 32382533 OWN - NLM STAT- MEDLINE DCOM- 20210211 LR - 20220414 IS - 2314-6141 (Electronic) IS - 2314-6133 (Print) VI - 2020 DP - 2020 TI - The Role of a Selective P2Y(6) Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms. PG - 1983940 LID - 10.1155/2020/1983940 [doi] LID - 1983940 AB - OBJECTIVE: The P2Y(6) receptor has been shown to be involved in many cardiovascular diseases, including hypertension and atherosclerosis. The study is aimed at exploring the role of the P2Y(6) receptor in Ang II-induced abdominal aortic aneurysm (AAA) formation in apolipoprotein E-deficient (apoE(-/-)) mice by using its selective antagonist. METHODS: Male apoE(-/-) mice were fed with high-fat diet and infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Mice were divided into four groups: normal saline (NS, placebo control) group (n = 8), Ang II+vehicle (Ang II) group (n = 14), Ang II-low dose MRS2578 (Ang II+MRS-16 mg) group (n = 14), and Ang II-high dose MRS2578 (Ang II+MRS-32 mg) group (n = 14). Daily intraperitoneal injection with vehicle or MRS2578 was pretreated one week before Ang II infusion. On postoperative day 10, aorta imaging of each group was taken by ultrasonography. After 4 weeks of Ang II infusion, the excised aortas were processed for diameter measurement and quantification of aneurysm severity and tissue characteristics; the blood samples were collected for measurement of the lipid profile and levels of cytokines. Verhoeff's Van Gieson (EVG) staining and immunochemistry staining were performed to evaluate disruption of the extracellular matrix (ECM) and infiltration of macrophages. Expression and activity of matrix metalloproteinases (MMPs) was measured by gelatin zymography. RESULTS: Treatment with MRS2578 made no significant difference in AAA formation, and maximal aortic diameter yet caused higher AAA rupture-induced mortality from 7% (Ang II) to 21.4% (Ang II+MRS-16 mg) or 42.9% (Ang II+MRS-32 mg), respectively (p < 0.05). Consistently, the severity of aneurysm tended to be more deteriorated in MRS2578-treated groups, especially the high-dosage group. The ratios of type III and IV aneurysm were much higher in the MRS2578-coadministered groups (p < 0.05). Furthermore, histological analyses showed that administration of MRS2578 significantly increased infiltration of macrophages, expression of monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and activities of MMP-2 and MMP-9 followed by aggravating degradation elastin in vivo (p < 0.05). However, the multiple effects of MRS2578 on the development of AAA are independent of changes in systolic blood pressure and lipid profiles. CONCLUSIONS: The present study demonstrated that administration of MRS2578 exacerbated the progression and rupture of experimental AAA through promoting proinflammatory response and MMP expression and activity, which indicated a crucial role of the P2Y(6) receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y(12) receptor antagonist had been successfully applied in clinical practice. Elucidating the underlying mechanisms of AAA and exploring potential therapeutic strategies are essential to prevent its progression and reduce the mortality rate. CI - Copyright (c) 2020 Xiao Du et al. FAU - Du, Xiao AU - Du X AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. FAU - Zhang, Shilan AU - Zhang S AD - Department of Gastroenterology, Central South University, Changsha, Hunan 410011, China. FAU - Xiang, Qunyan AU - Xiang Q AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. FAU - Chen, Jingyuan AU - Chen J AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. FAU - Tian, Feng AU - Tian F AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. FAU - Xu, Jin AU - Xu J AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. FAU - Li, Xin AU - Li X AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. FAU - Tan, Yuansheng AU - Tan Y AD - Ministry of Education, Hospital of Hunan University of Traditional Chinese Medicine, Changsha, Hunan 410011, China. FAU - Liu, Ling AU - Liu L AUID- ORCID: 0000-0001-6979-701X AD - Department of Cardiovascular Medicine, Central South University, Changsha, Hunan 410011, China. LA - eng PT - Journal Article DEP - 20200416 PL - United States TA - Biomed Res Int JT - BioMed research international JID - 101600173 RN - 0 (Isothiocyanates) RN - 0 (N,N''-1,4-butanediylbis(N'-(3-isothiocyanatophenyl))thiourea) RN - 0 (Purinergic Antagonists) RN - 0 (Receptors, Purinergic P2) RN - 0 (purinoceptor P2Y6) RN - 11128-99-7 (Angiotensin II) RN - GYV9AM2QAG (Thiourea) SB - IM EIN - Biomed Res Int. 2020 Sep 26;2020:8569421. PMID: 33062703 MH - *Angiotensin II/adverse effects/pharmacology MH - Animals MH - *Aortic Aneurysm, Abdominal/chemically induced/metabolism/pathology MH - Disease Models, Animal MH - *Isothiocyanates/adverse effects/pharmacology MH - Mice MH - Mice, Knockout, ApoE MH - *Purinergic Antagonists/adverse effects/pharmacology MH - Receptors, Purinergic P2/*metabolism MH - Thiourea/adverse effects/*analogs & derivatives/pharmacology PMC - PMC7184271 COIS- The authors declared that they have no conflicts of interest to this work. EDAT- 2020/05/10 06:00 MHDA- 2021/02/12 06:00 PMCR- 2020/04/18 CRDT- 2020/05/09 06:00 PHST- 2019/12/03 00:00 [received] PHST- 2020/03/10 00:00 [revised] PHST- 2020/03/23 00:00 [accepted] PHST- 2020/05/09 06:00 [entrez] PHST- 2020/05/10 06:00 [pubmed] PHST- 2021/02/12 06:00 [medline] PHST- 2020/04/18 00:00 [pmc-release] AID - 10.1155/2020/1983940 [doi] PST - epublish SO - Biomed Res Int. 2020 Apr 16;2020:1983940. doi: 10.1155/2020/1983940. eCollection 2020.