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Korean Circ J. 2019 Jul;49(7):615-626. English. Original Article. https://doi.org/10.4070/kcj.2018.0379
Kim I , Park CS , Lee HY .
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. hylee612@snu.ac.kr
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
Abstract

Background and Objectives

Angiotensin II (Ang II) has been suggested to accelerate vascular senescence, however the molecular mechanism(s) remain unknown.

Methods

We cultured human coronary artery smooth muscle cells (hCSMCs) and treated Ang II and/or fimasartan. Or we transfected adenoviral vectors expressing CYR61 (Ad-CYR61) or antisense CYR61 (Ad-As-CYR61). Cellular senescence was evaluated senescence-associated β-galactosidase (SA-β-gal) assay. The molecular mechanisms were investigated real-time PCR and western blots.

Results

SA-β-gal-positive cells significantly increased in Ang II-treated hCSMCs (5.77±1.43-fold compared with the control). The effect of Ang II was significantly attenuated by pretreatment with the Ang II type 1 receptor blocker, fimasartan (2.00±0.92-fold). The expression of both p53 and p16 senescence regulators was significantly increased by Ang II (p53: 1.39±0.17, p16: 1.19±0.10-fold vs. the control), and inhibited by fimasartan. Cysteine-rich angiogenic protein 61 (CYR61) was rapidly induced by Ang II. Compared with the control, Ad-CYR61-transfected hCSMCs showed significantly increased SA-β-gal-positive cells (3.47±0.65-fold). Upon transfecting Ad-AS-CYR61, Ang II-induced senescence (3.74±0.23-fold) was significantly decreased (1.77±0.60-fold). p53 expression by Ang II was significantly attenuated by Ad-AS-CYR61, whereas p16 expression was not regulated. Ang II activated ERK1/2 and p38 MAPK, which was significantly blocked by fimasartan. ERK and p38 inhibition both regulated Ang II-induced CYR61 expression. However, p53 expression was only regulated by ERK1/2, whereas p16 expression was only attenuated by p38 MAPK.

Conclusions

Ang II induced vascular senescence by the ERK/p38 MAPK–CYR61 pathway and ARB, fimasartan, protected against Ang II-induced vascular senescence.

Copyright © 2019. Korean Association of Medical Journal Editors.