Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity

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Abstract

Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT ₁R). 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 AT ₁R, AT ₂R 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.

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Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis.

Zhao-Jun Liu, Yurong Tan, Gary W. Beecham … (2012)

Notch signaling plays pivotal roles in the pathogenesis of vascular disease. However, little is known about its role in atherosclerosis. We sought to investigate the potential involvement of the Notch signaling in atherosclerosis. Expression of Notch pathway components in mouse and human aorta with or without atherosclerosis plaque was examined by immunohistochemistry. Expression of Notch target genes in young versus aged human endothelial cells (EC) was examined by PCRArray and immunoblot. In vitro loss- and gain-of-function approaches were utilized to evaluate the role of Notch signaling in inducing EC senescence and secretion of pro-inflammatory cytokines by ProteinArray. Notch gene profile was studied in 1054 blood samples of patients with coronary artery disease (CAD). Genotyping was performed using the Genome-Wide Single Nucleotide Polymorphism (SNP) Array. Notch pathway components were upregulated in luminal EC at atherosclerotic lesions from mouse and human aortas. In addition, the Notch pathway was activated in aged but not young human EC. Enforced Notch activation resulted in EC senescence and significantly upregulated expression of several molecules implicated in the inflammatory response (IL-6/IL-8/IL-1α/RANTES/ICAM-1). The upregulated IL-6 was partially responsible for mediating leukocyte transendothelial migration. Genetic association analysis detected, of 82 SNPs across 6 Notch pathway genes analyzed, 4 SNPs with nominal association with CAD burden. Notch pathway is activated in luminal EC at atherosclerotic plaques and results in pro-inflammatory response and senescence of EC. Notch signaling may be linked to human CAD risk. These findings implicate a potential involvement of Notch signaling in atherosclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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Angiotensin II Requires Zinc and Downregulation of the Zinc Transporters ZnT3 and ZnT10 to Induce Senescence of Vascular Smooth Muscle Cells

Nikolay Patrushev, Bonnie Seidel-Rogol, Gloria Salazar (2012)

Senescence, a hallmark of mammalian aging, is associated with the onset and progression of cardiovascular disease. Angiotensin II (Ang II) signaling and zinc homeostasis dysfunction are increased with age and are linked to cardiovascular disease, but the relationship among these processes has not been investigated. We used a model of cellular senescence induced by Ang II in vascular smooth muscle cells (VSMCs) to explore the role of zinc in vascular dysfunction. We found that Ang II-induced senescence is a zinc-dependent pathway mediated by the downregulation of the zinc transporters ZnT3 and ZnT10, which work to reduce cytosolic zinc. Zinc mimics Ang II by increasing reactive oxygen species (ROS), activating NADPH oxidase activity and Akt, and by downregulating ZnT3 and ZnT10 and inducing senescence. Zinc increases Ang II-induced senescence, while the zinc chelator TPEN, as well as overexpression of ZnT3 or ZnT10, decreases ROS and prevents senescence. Using HEK293 cells, we found that ZnT10 localizes in recycling endosomes and transports zinc into vesicles to prevent zinc toxicity. Zinc and ZnT3/ZnT10 downregulation induces senescence by decreasing the expression of catalase. Consistently, ZnT3 and ZnT10 downregulation by siRNA increases ROS while downregulation of catalase by siRNA induces senescence. Zinc, siZnT3 and siZnT10 downregulate catalase by a post-transcriptional mechanism mediated by decreased phosphorylation of ERK1/2. These data demonstrate that zinc homeostasis dysfunction by decreased expression of ZnT3 or ZnT10 promotes senescence and that Ang II-induced senescence is a zinc and ROS-dependent process. Our studies suggest that zinc might also affect other ROS-dependent processes induced by Ang II, such as hypertrophy and migration of smooth muscle cells.

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CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction.

Christian Becker, Swenja Kröller-Schön, Kerstin Jurk … (2013)

CD40 ligand (CD40L) is involved in the vascular infiltration of immune cells and pathogenesis of atherosclerosis. Additionally, T cell CD40L release causes platelet, dendritic cell and monocyte activation in thrombosis. However, the role of CD40L in angiotensin II (ATII)-driven vascular dysfunction and hypertension remains incompletely understood. We tested the hypothesis that CD40L contributes to ATII-driven vascular inflammation by promoting platelet-leukocyte activation, vascular infiltration of immune cells and by amplifying oxidative stress. C57BL/6 and CD40L-/- mice were infused with ATII (1 mg/kg/day for 7 days) using osmotic minipumps. Vascular function was recorded by isometric tension studies, and reactive oxygen species (ROS) were monitored in blood and heart by optical methods. Western blot, immunohistochemistry, FACS analysis and real-time RT-PCR were used to analyze immune cell distribution, pro-inflammatory cytokines, NAPDH oxidase subunits, T cell transcription factors and other genes of interest. ATII-treated CD40L-/- mice showed improved endothelial function, suppression of blood platelet-monocyte interaction (FACS), platelet thrombin generation (calibrated automated thrombography) and coagulation (bleeding time), as well as decreased oxidative stress in the aorta, heart and blood compared to wild-type mice. Moreover, ATII-treated CD40L-/- mice displayed decreased levels of TH1 cytokines released by splenic CD4⁺ T cells (ELISA) and lower expression levels of NOX-2, T-bet and P-selectin as well as diminished immune cell infiltration in aortic tissue compared to controls. Our results demonstrate that many ATII-induced effects on vascular dysfunction, such as vascular inflammation, oxidative stress and a pro-thrombotic state, are mediated at least in part via CD40L.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Mol Med

Journal ID (iso-abbrev): J. Cell. Mol. Med

Journal ID (publisher-id): jcmm

Title: Journal of Cellular and Molecular Medicine

Publisher: John Wiley & Sons, Ltd (Chichester, UK )

ISSN (Print): 1582-1838

ISSN (Electronic): 1582-4934

Publication date (Print): June 2014

Publication date (Electronic): 18 February 2014

Volume: 18

Issue: 6

Pages: 1071-1080

Affiliations

[a ]Department of Gerontology, The First Affiliated Hospital of China Medical University Shenyang, Liaoning Province, China

[b ]Center Laboratory Technology and Experimental Medicine, China Medical University Shenyang, Liaoning Province, China

[c ]Department of Epidemiology, School of Public Health, China Medical University Shenyang, Liaoning Province, China

Author notes

* Correspondence to: Professor Haiyan SHAN, Department of Gerontology, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North street, Heping District, Shenyang, Liaoning Province 110001, China., Tel.: 86-024-83282776, Fax: 86-024-83282693, E-mail: shanhy024@ 123456163.com

Article

DOI: 10.1111/jcmm.12251

PMC ID: 4508146

PubMed ID: 24548645

SO-VID: 60b65851-4d8b-4621-a679-15906d05ff8e

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity

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Most cited references 32

Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis.

Angiotensin II Requires Zinc and Downregulation of the Zinc Transporters ZnT3 and ZnT10 to Induce Senescence of Vascular Smooth Muscle Cells

CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction.

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