Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial
dysfunction induced by pressure overload.
Authors Symons JD, Hu P, Yang Y, Wang X, Zhang QJ, Wende AR, Sloan CL, Sena S, Abel ED,
Litwin SE
Submitted By E. Dale Abel on 5/2/2011
Status Published
Journal American journal of physiology. Heart and circulatory physiology
Year 2011
Date Published 1/1/2011
Volume : Pages 300 : H374 - H381
PubMed Reference 20971769
Abstract Ablating insulin receptors in cardiomyocytes causes subendocardial fibrosis and
left ventricular (LV) dysfunction after 4 wk of transverse aortic constriction
(TAC). To determine whether these maladaptive responses are precipitated by
coronary vascular dysfunction, we studied mice with cardiomyocyte-restricted
knock out of insulin receptors (CIRKO) and wild-type (WT) TAC mice before the
onset of overt LV dysfunction. Two weeks of TAC produced comparable increases (P
< 0.05 vs. respective sham) in heart weight/body weight (mg/g) in WT-TAC (8.03 ±
1.14, P < 0.05 vs. respective sham) and CIRKO-TAC (7.76 ± 1.25, P < 0.05 vs.
respective sham) vs. WT-sham (5.64 ± 0.11) and CIRKO-sham (4.64 ± 0.10) mice. In
addition, 2 wk of TAC were associated with similar LV geometry and function
(echocardiography) and interstitial fibrosis (picrosirius red staining) in CIRKO
and WT mice. Responses to acetylcholine (ACh), N(G)-monomethyl-L-arginine
(l-NMMA), and sodium nitroprusside (SNP) were measured in coronary arteries that
were precontracted to achieve ~70% of maximal tension development using the
thromboxane A(2) receptor mimetic U-46619 (~3 × 10(-6) M). ACh-evoked
vasorelaxation was absent in WT-TAC but was present in CIRKO-TAC albeit reduced
relative to sham-operated animals. l-NMMA-evoked tension development was similar
in vessels from CIRKO-TAC mice but was lower (P < 0.05) in WT-TAC animals vs.
the respective sham-operated groups, and SNP-evoked vasorelaxation was similar
among all mice. Thus estimates of stimulated and basal endothelial nitric oxide
release were better preserved in CIRKO vs. WT mice in response to 2 wk of TAC.
These findings indicate that maladaptive LV remodeling previously observed in
CIRKO-TAC mice is not precipitated by coronary artery dysfunction, because CIRKO
mice exhibit compensatory mechanisms (e.g., increased eNOS transcript and
protein) to maintain coronary endothelial function in the setting of pressure

Investigators with authorship
E. Dale AbelUniversity of Iowa