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Cited by 61Cardiac Fibrosis and RemodelingCardiovascular Function and Risk FactorsCardiomyopathy and Myosin Studies

Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density

McQueen, Alfred P., Zhang, Dongfang, Hu, Ping, Swenson, LeAnne, Yang, Ying, Zaha, Vlad G., Hoffman, James L., Yun, Ui Jeong +2 more·2005·Journal of Molecular and Cellular Cardiology
DOI 10.1016/j.yjmcc.2005.07.017
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Abstract

Diabetics have worse outcomes than nondiabetics after a variety of cardiac insults. We tested the hypothesis that impaired insulin receptor signaling in myocytes worsens cardiac remodeling and function following injury, even in the absence of hyperglycemia. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wild type (WT) mice were treated with isoproterenol (ISO) for 2 or 5 days. Heart rates and cardiac mass increased comparably following ISO in WT and CIRKO mice. After 5 days, WT hearts were hyperdynamic by echocardiographic and left ventricular pressure measurements. However, CIRKO hearts had a blunted increase in contractility and relaxation following ISO. Interestingly, single myocytes isolated from both CIRKO ISO and WT ISO hearts had increased cellular shortening with prolonged time to peak shortening vs. respective shams. Thus, loss of myocytes or extramyocyte factors, rather than intrinsic dysfunction of surviving myocytes, caused the blunted inotropic response in ISO treated CIRKO hearts. Indeed, CIRKO ISO mice had increased troponin release after 2 days and greater interstitial and sub-endocardial fibrosis at 5 days than did ISO WT. Apoptosis assessed by TUNEL and caspase staining was increased in CIRKO ISO compared to WT ISO hearts; however, very few of the apoptotic nuclei were clearly in cardiac myocytes. After 5 days of ISO treatment, VEGF expression was increased in WT but not in CIRKO hearts. In keeping with this finding, capillary density was reduced in CIRKO ISO relative to WT ISO. Basal expression of hypoxia-inducible factor-1alpha was lower in CIRKO vs. WT hearts and may explain the blunted VEGF response. Thus, absence of insulin receptor signaling in the cardiac myocyte worsens catecholamine-mediated myocardial injury, at least in part, via mechanisms that tend to impair myocardial blood flow and increase ischemic injury.

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Crossref · 10.1016/j.yjmcc.2005.07.017

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  • Insulin receptor-deficient hearts have increased susceptibility to injury when exposed to hypertrophic stimuli such as pressure overload and chronic adrenergic stimulation with isoproterenol.

    “Insulin receptor-deficient hearts also have increased susceptibility to injury when exposed to hypertrophic stimuli such as pressure overload and chronic adrenergic stimulation with isoproterenol (150, 231).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [231]

  • Insulin signaling promotes angiogenesis in the heart.

    “Studies in isoproterenol-treated CIRKO hearts also highlighted the important role of insulin signaling in promoting angiogenesis in the heart (231).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [231]

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Authors
McQueen, A. P., Zhang, D., Hu, P., Swenson, L., Yang, Y., Zaha, V. G., Hoffman, J. L., Yun, U. J., Chakrabarti, G., & Wang, Z.
Affiliations
University of Utah (US)
ORCID
Venue
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier BV
Published
2005-12
Volume
39
Issue
6
Pages
882-892
ISSN
0022-2828 (ISSN-L)
DOI
10.1016/j.yjmcc.2005.07.017
OpenAlex
W2133615731
Cited by
61
References
36
Citations by year
2023: 2 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 5
FWCI
3.19
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular and Cellular Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • National Institutes of Health
  • U.S. Public Health Service (U01-70525)
  • National Heart, Lung, and Blood Institute (HL 70070, T32-HL-7576, T35 HL 07744, R01HL070070, HL-52338-06, P50HL052338, T35HL007744, T32HL007576)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK/HL58073, R01DK092065)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
insulin receptor signaling, cardiac contractility, diabetic cardiomyopathy, capillary density, myocardial ischemia, vascular endothelial growth factor, hypoxia-inducible factor-1α, myocardial fibrosis, apoptosis, cardiac remodeling, myocardial blood flow
MeSH terms
Animals, Capillaries, Cardiotonic Agents, Coronary Circulation, Fibrosis, Gene Expression Regulation, Cardiomegaly, Heart Rate, Humans, Isoproterenol, Male, Receptor, Insulin, Signal Transduction, Apoptosis, Mice, Knockout, Myocytes, Cardiac, Diabetes Complications, Mice

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