Abstract
Objective The P2Y6 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 P2Y6 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 P2Y6 receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y12 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.
Highlights
Abdominal aortic aneurysm (AAA) is a permanent, degenerative vascular disease, characterized by localized enlargement of the abdominal aorta exceeding the normal vascular diameter by more than 50% [1]
Available evidence suggests that it is associated with increased infiltration of macrophages in arterial walls driven by inflammatory factors, such as vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein 1 (MCP-1), and obvious degradation of the extracellular matrix (ECM) caused by activated matrix metalloproteinases (MMPs) and apoptosis of medial vascular smooth muscle cells (VSMCs) [1, 7,8,9]
To investigate the role of the P2Y6 receptor in AAA formation, 16~32 mg MRS2578, the specific P2Y6 receptor antagonist, or vehicle was administrated via intraperitoneal injection 1 week before Ang II+vehicle (Ang II) infusion
Summary
Abdominal aortic aneurysm (AAA) is a permanent, degenerative vascular disease, characterized by localized enlargement of the abdominal aorta exceeding the normal vascular diameter by more than 50% [1]. In spite of high mortality and morbidity, AAA is often asymptomatic in its earliest stage. Once the aneurysm is larger than 5.5 cm in size, surgical repair is the only applicable treatment to reduce the mortality of AAA even with a considerable perioperative risk [2]. Most patients with AAA have relatively small aneurysms that are incompatible with surgical indications, and effective drugs are needed to delay progression and prevent rupture of AAA [3, 4]. It has been established that the typically pathologic feature of AAA in both animal models and patients is chronic vascular inflammation [5, 6]. Available evidence suggests that it is associated with increased infiltration of macrophages in arterial walls driven by inflammatory factors, such as vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein 1 (MCP-1), and obvious degradation of the extracellular matrix (ECM) caused by activated matrix metalloproteinases (MMPs) and apoptosis of medial vascular smooth muscle cells (VSMCs) [1, 7,8,9]
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