Journal article
Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload
American journal of physiology. Heart and circulatory physiology, Vol.300(1), pp.H374-H381
01/2011
DOI: 10.1152/ajpheart.01200.2009
PMCID: PMC3023253
PMID: 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 overload.
Details
- Title: Subtitle
- Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload
- Creators
- J. David Symons - College of Health, University of Utah, Salt Lake City; andPing Hu - Division of Cardiology, andYing Yang - Division of Cardiology, andXiaohui Wang - Division of Cardiology, andQuan-Jiang Zhang - College of Health, University of Utah, Salt Lake City; andAdam R Wende - Division of Endocrinology, Metabolism, and DiabetesCrystal L Sloan - Division of Endocrinology, Metabolism, and DiabetesSandra Sena - Division of Endocrinology, Metabolism, and DiabetesE. Dale Abel - Division of Endocrinology, Metabolism, and DiabetesSheldon E Litwin - Division of Cardiology, and
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.300(1), pp.H374-H381
- DOI
- 10.1152/ajpheart.01200.2009
- PMID
- 20971769
- PMCID
- PMC3023253
- NLM abbreviation
- Am J Physiol Heart Circ Physiol
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Publisher
- American Physiological Society; Bethesda, MD
- Language
- English
- Date published
- 01/2011
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025259102771
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