Cited by 70Renin-Angiotensin System StudiesCardiac Fibrosis and RemodelingCardiovascular Disease and Adiposity

Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity

Zaman, A.K.M.Tarikuz, Fujii, Satoshi, Goto, Daisuke, Furumoto, Tomoo, Mishima, Tetsuya, Nakai, Yukihito, Dong, Jie, Imagawa, Shogo +2 more·2004·Journal of Molecular and Cellular Cardiology

Abstract

Obesity and insulin resistance confer increased risk for accelerated coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular fibrosis in genetically obese mice that develop insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of angiotensin II (Ang) II. Genetically obese ob/ob mice were given ACE inhibitor (temocapril) or Ang II type 1 (AT(1)) receptor blocker (olmesartan) from 10 to 20 weeks. Cardiac expressions of plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and transforming growth factor (TGF)-beta(1), a prototypic profibrotic molecule, were determined and extent of perivascular coronary fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of PAI-1 and TGF-beta(1) compared with the values in lean counterpart. Perivascular coronary fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular collagen as measured by hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular type 1 collagen. Markedly increased PAI-1 and TGF-beta were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with temocapril or olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular fibrosis, plasma PAI-1 and TGF-beta(1), left ventricular collagen and mural immunoreactivity for PAI-1, TGF-beta and collagen type 1. The c-Jun NH(2)-terminal kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by temocapril and olmesartan. Ang II-mediated upregulation of PAI-1 and TGF-beta(1) with collagen deposition may explain the mechanism of perivascular fibrosis in obese mice. ACE inhibition and blockade of AT(1) receptor may prevent coronary perivascular fibrosis and collagen deposition even before development of overt diabetes. JNK activation may be a mediator of obesity-related cardiac dysfunction and a potential therapeutic target.

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Crossref · 10.1016/j.yjmcc.2004.05.006

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  • In ob/ob mice, fibrosis occurs mainly in the coronary perivascular region.

    “In ob/ob mice, fibrosis occurs mainly in the coronary perivascular region (391, 392).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [391]

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Authors
Zaman, A. K. M. T., Fujii, S., Goto, D., Furumoto, T., Mishima, T., Nakai, Y., Dong, J., Imagawa, S., Sobel, B. E., & Kitabatake, A.
Affiliations
  • Hokkaido University (JP)
  • University of Vermont (US)
Corresponding author
Fujii, Satoshi
Venue
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier BV
Published
2004-08
Volume
37
Issue
2
Pages
525-535
ISSN
0022-2828 (ISSN-L)
OpenAlex
W2116549196
Cited by
70
References
42
Citations by year
2026: 2 · 2025: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 3
FWCI
1.96
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Molecular and Cellular Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Ministry of Education, Culture, Sports, Science and Technology
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
Keywords
angiotensin II, insulin resistance, obesity, angiotensin-converting enzyme inhibition, angiotensin II type 1 receptor blockade, temocapril, olmesartan, plasminogen activator inhibitor-1, TGF-β1, c-Jun NH2-kinase, ob/ob mice, cardiomyopathy
MeSH terms
Olmesartan Medoxomil, Angiotensin II, Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Glucose, Coronary Disease, Coronary Vessels, Fibrosis, Heart Ventricles, Imidazoles, Insulin, Insulin Resistance, Male, Mice, Obese, Obesity, Phosphorylation, Tetrazoles, Thiazepines, Transforming Growth Factor beta, Plasminogen Activator Inhibitor 1, Matrix Metalloproteinase 9, Collagen Type I, Angiotensin II Type 1 Receptor Blockers, JNK Mitogen-Activated Protein Kinases, Mice

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