Abstract
Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT1R). However, the role and underlying mechanisms of AT1R in ageing-related vascular degeneration are not well understood. In this study, 40 ageing rats were randomly divided into two groups: ageing group which received no treatment (ageing control), and valsartan group which took valsartan (selective AT1R blocker) daily for 6 months. 20 young rats were used as adult control. The aorta structure were analysed by histological staining and electron microscopy. Bcl-2/Bax expression in aorta was analysed by immunohistochemical staining, RT-PCR and Western blotting. The expressions of AT1R, AT2R and mitogen-activated protein kinases (MAPKs) were detected. Significant structural degeneration of aorta in the ageing rats was observed, and the degeneration was remarkably ameliorated by long-term administration of valsartan. With ageing, the expression of AT1R was elevated, the ratio of Bcl-2/Bax was decreased and meanwhile, an important subgroup of MAPKs, extracellular signal-regulated kinase (ERK) activity was elevated. However, these changes in ageing rats could be reversed to some extent by valsartan. In vitro experiments observed consistent results as in vivo study. Furthermore, ERK inhibitor could also acquire partial effects as valsartan without affecting AT1R expression. The results indicated that AT1R involved in the ageing-related degeneration of aorta and AT1R-mediated ERK activity was an important mechanism underlying the process.
Highlights
Ultrastructural degeneration of aorta with ageing and the effect of valsartan Ultrastructural analysis of aorta was focused on vascular endothelial cells, because the senescent endothelial cells may critically disturb the integrity of the endothelial monolayer and may thereby contribute to vascular injury and atherosclerosis [15,16,17,18,19].The endothelial cell in control group showed a fusiform, smooth shape and even chromatin (Fig. 1A)
To test whether AT1R-mediated p-extracellular signal-regulated kinase (ERK) activity is correlated with aorta injury during ageing, we investigated the protective effect of ERK inhibitor on ageing rat-derived aorta endothelial cells and compared it with valsartan
Clarifying the mechanisms underlying the ageing-induced vascular injury is of great significance for prevention and attenuation of such diseases
Summary
Population ageing is a worldwide problem. In the United States, there are 35 million people of more than 65 years old. In the process of ageing, many physiological functions will be impaired or degenerate, resulting in a number of detrimental consequences for human health [2, 3]. Data have demonstrated that Ang II played an important role in vascular ageing as well as in the initiation and progression of atherosclerosis [8, 9]. In the past decades, independent groups have focused on Ang II as a mediator of vascular cell dysfunction in various cardiovascular disorders [10, 11]. The mechanisms that involved in the Ang II-mediated vascular injury in several cardiovascular diseases were partially revealed, e.g. Ang II causes arteriolar vasoconstriction, superoxide anion production and endothelin release through its type 1 receptor (AT1R), resulting in a 2014 The Authors
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