Contractile dysfunction in hypertrophied hearts with deficient insulin receptor
signaling: possible role of reduced capillary density
Authors Alfred P. McQueen, Dongfang Zhang, Ping Hu, LeAnne Swenson, Ying Yang, Vlad G.
Zaha, James L. Hoffman, Ui Jeong Yun, Gopa Chakrabarti, ZhengmingWang, Kurt H.
Albertine, E. Dale Abel, Sheldon E. Litwin
Submitted By E. Dale Abel on 11/9/2005
Status Published
Journal Journal of molecular and cellular cardiology
Year 2005
Date Published 12/1/2005
Volume : Pages 39 : 882 - 892
PubMed Reference 16216265
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 andWT 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 ISOWT.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 toWT ISO. Basal expression of hypoxia-inducible factor-1a
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.

Investigators with authorship
E. Dale AbelUniversity of Iowa