Role of TGF-β1/Smads pathway in carotid artery remodeling in renovascular hypertensive rats and prevention by Enalapril and Amlodipine

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Abstract

Objective

To investigate the role of transforming growth factor-β1 (TGF-β1), Smad2/3 and Smad7 expressions in carotid artery remodeling in renovascular hypertensive rats, and also the therapeutic effect of Enalapril and Amlodipine.

Methods

The renovascular hypertensive rat (RHR) models with “two-kidney and one-clip” were established, including model group ( n = 6), sham-operated group ( n = 6), Enalapril group (10 mg/kg per day, n = 6), Amlodipine group (5 mg/kg per day, n = 6) and combination group (Amlodipine 2.5 mg/kg per day + Enalapril 5mg/kg per day, n = 6). The medication were continuous administrated for six weeks. Carotid artery morphological and structural changes in the media were observed by HE staining, Masson staining and immuno histochemical staining. Media thickness (MT), MT and lumen diameter ratio (MT/LD), and the expression levels of media α-smooth muscle actin (α-actin), proliferating cell nuclear antigen (PCNA), TGF-β1, phosphorylated Smad2/3 (p-Smad2/3) and Smad7 in carotid arteries were measured.

Results

The media of carotid arteries in RHR model group was significantly thickened, the volume of smooth muscle cell was increased, and the array was in disorder; MT, MT/LD, the proliferation index of smooth muscle cell and collagen fiber area percentage of carotid arteries in the model group were significantly higher than those in the sham-operated group ( P < 0.01). Compared to sham-operated group, the model group had significantly higher expressions of TGF-β1 and p-Smad2/3 ( P < 0.05) and lower Smad7 expression. Both Enalapril and Amlodipine improved smooth muscle hypertrophy and collagen deposition, reduced RHR carotid MT, MT/LD, proliferation index of smooth muscle cell, collagen fiber area percentage and the expressions of TGF-β1 and p-Smad2/3 ( P < 0.05), increased Smad7 expression ( P < 0.05). Moreover, the combination treatment of Enalapril and Amlodipine had significantly better effects than single Amlodipine group ( P < 0.05), but not single Enalapril group.

Conclusions

TGF-β1/Smads pathway may participate in the mechanism of carotid artery remodeling in RHR; the role of Amlodipine and Enalapril in inversing carotid artery remodeling may be related to the change of TGF-β1/Smads pathway, the combination treatment of Amlodipine and Enalapril had better effects than single administration of Amlodipine.

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Most cited references 18

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Essential role of Smad3 in angiotensin II-induced vascular fibrosis.

Erwin P Bottinger, Wenjun Ju, Chuxia Deng … (2006)

Angiotensin II (Ang II) plays a pivotal role in vascular fibrosis, which leads to serious complications in hypertension and diabetes. However, the underlying signaling mechanisms are largely unclear. In hypertensive patients, we found that arteriosclerosis was associated with the activation of Smad2/3. This observation was further investigated in vitro by stimulating mouse primary aorta vascular smooth muscle cells (VSMCs) with Ang II. There were several novel findings. First, Ang II was able to activate an early Smad signaling pathway directly at 15 to 30 minutes. This was extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) dependent but transforming growth factor-beta (TGF-beta) independent because Ang II-induced Smad signaling was blocked by addition of ERK1/2 inhibitor and by dominant-negative (DN) ERK1/2 but not by DN-TGF-beta receptor II (TbetaRII) or conditional deletion of TbetaRII. Second, Ang II was also able to activate the late Smad2/3 signaling pathway at 24 hours, which was TGF-beta dependent because it was blocked by the anti-TGF-beta antibody and DN-TbetaRII. Finally, activation of Smad3 but not Smad2 was a key and necessary mechanism of Ang II-induced vascular fibrosis because Ang II induced Smad3/4 promoter activities and collagen matrix expression was abolished in VSMCs null for Smad3 but not Smad2. Thus, we concluded that Ang II induces vascular fibrosis via both TGF-beta-dependent and ERK1/2 MAPK-dependent Smad signaling pathways. Activation of Smad3 but not Smad2 is a key mechanism by which Ang II mediates arteriosclerosis.

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TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.

Jo el J Schultz, Stacey Nix, Peter J. Reiser … (2002)

Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-beta1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-beta1-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang II treatment. In contrast, Ang II-treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II-treated wild-type mice but unchanged in Ang II-treated TGF-beta1-deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II-treated mice. Atrial natriuretic factor expression was approximately 6-fold elevated in Ang II-treated wild-type, but not TGF-beta1-deficient mice. However, the alpha- to beta-myosin heavy chain switch did not occur in Ang II-treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-beta1. The Ang II effect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-beta1 is an important mediator of the hypertrophic growth response of the heart to Ang II.

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Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-beta(1).

B. Williams, Michael J O’Callaghan (2000)

Elevated blood pressure imposes increased mechanical stress on the vascular wall, and mechanical strain is a mitogenic stimulus for vascular smooth muscle (VSM) cells. The role of mechanical forces in regulating the production of noncellular material by VSM cells for VSM cells of human origin remains undefined. We thus investigated the effects of chronic cyclical mechanical strain on extracellular matrix (ECM) protein production by cultured human VSM cells. To simulate a blood pressure of 120/80 mm Hg, human VSM cells were repetitively stretched and relaxed by 10% to 16% of their original length with the Flexercell apparatus. Fibronectin and collagen protein concentrations, matrix metalloproteinase (MMP) activity, and transforming growth factor-beta(1) (TGF-beta(1)) mRNA expression by human VSM cells were measured in response to mechanical strain. Exposing human VSM cells to 5 days of chronic cyclical mechanical strain increased fibronectin (+48%, P:<0.01) and collagen (+50%, P:<0.001) concentrations when compared with cells grown in static conditions. Mechanical strain also increased MMP-2 activity, the predominant matrix-degrading isoform (+11%, P:<0.05) in human VSM cells, thus strain-induced ECM accumulation was not due to inhibition of ECM protein degradation. Strain also increased TGF-beta(1) mRNA expression and the production of a soluble factor that increased ECM protein production. Moreover, a TGF-beta-blocking antibody inhibited the effect of strain-conditioned media on matrix production by human VSM cells. These results suggest that chronic cyclical mechanical strain can directly modulate the fibrogenic activity of human VSM cells by inducing ECM protein synthesis and MMP activity. This occurs, at least in part, through mechanical strain-induced TGF-beta(1) production, a mechanism that could explain the increased vascular ECM deposition in hypertension.

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Author and article information

Journal

Journal ID (nlm-ta): J Geriatr Cardiol

Journal ID (iso-abbrev): J Geriatr Cardiol

Journal ID (publisher-id): JGC

Title: Journal of Geriatric Cardiology : JGC

Publisher: Science Press

ISSN (Print): 1671-5411

Publication date (Print): June 2012

Volume: 9

Issue: 2

Pages: 185-191

Affiliations

[1 ]Institute of Clinical Medicine, Zunyi Medical College, Zunyi 563003, Guizhou Province, China

[2 ]Department of Cardiology, Affiliated Hospital of Zunyi Medical College, Zunyi 563003, Guizhou Province, China

[3 ]Department of Pathology, Affiliated Hospital of Zunyi Medical College, Zunyi 563003, Guizhou Province, China

Author notes

Correspondence to: Qian-Hui Shang, Institute of Clinical Medicine, Zunyi Medical College, Zunyi 563003, Guizhou Province, China. E-mail: qianhui-shang@ 123456hotmail.com

Article

Publisher ID: jgc-09-02-185

DOI: 10.3724/SP.J.1263.2012.04011

PMC ID: 3418910

PubMed ID: 22916067

SO-VID: 9afd1c4f-383b-45b9-8848-32f8da90ecc7

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

History

Date received : 1 April 2012

Date revision received : 25 May 2012

Date accepted : 1 June 2012

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Role of TGF-β1/Smads pathway in carotid artery remodeling in renovascular hypertensive rats and prevention by Enalapril and Amlodipine

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Abstract

Objective

Methods

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Conclusions

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Karger: Cardiovascular System

Most cited references 18

Essential role of Smad3 in angiotensin II-induced vascular fibrosis.

TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.

Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-beta(1).

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