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

Alfred P. McQueen, Dongfang Zhang, Ping Hu, Le Anne Swenson, Ying Yang, Vlad G. Zaha, James L. Hoffman, Jeong Yun Ui, Gopa Chakrabarti, Zhengming Wang, Kurt H. Albertine, E. D. Abel, Sheldon E. Litwin

Research output: Contribution to journalArticle

42 Scopus citations

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-1α 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.

Original languageEnglish (US)
Pages (from-to)882-892
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number6
DOIs
StatePublished - Dec 1 2005

Keywords

  • Capillary density
  • Cardiac hypertrophy
  • Diabetes
  • Heart
  • Insulin resistance
  • Isoproterenol
  • Knockout mouse
  • Mouse model

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    McQueen, A. P., Zhang, D., Hu, P., Swenson, L. A., Yang, Y., Zaha, V. G., Hoffman, J. L., Ui, J. Y., Chakrabarti, G., Wang, Z., Albertine, K. H., Abel, E. D., & Litwin, S. E. (2005). Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: Possible role of reduced capillary density. Journal of Molecular and Cellular Cardiology, 39(6), 882-892. https://doi.org/10.1016/j.yjmcc.2005.07.017