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 P.; Yun, Ui Jeong; Chakrabarti, Gopa; Wang, Zhengming

doi:10.1016/j.yjmcc.2005.07.017

Cited by 59 publications

(45 citation statements)

References 33 publications

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“…In experimental rodent models, myocardial contractile dysfunction independent of coronary artery disease has also been demonstrated in db/db, ob/ob, and Zucker rodent models, supporting the existence of an obesity-related cardiomyopathy and a diabetic cardiomyopathy (3,22). In addition, mice with a selective cardiomyocyte only deletion of the insulin receptor (CIRKO mice) have reduced insulinstimulated glucose uptake and also have a modest decrease in contractile function, thereby implicating insulin resistance as a contributing factor in the development of contractile dysfunction in the metabolic syndrome (23,24).…”

Section: Diabetic Cardiomyopathymentioning

confidence: 88%

Insulin Resistance and Cardiomyopathy

Huang¹,

Hung²

2012

Cardiomyopathies - From Basic Research to Clinical Management

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Section: Diabetic Cardiomyopathymentioning

confidence: 88%

Insulin Resistance and Cardiomyopathy

Huang¹,

Hung²

2012

Cardiomyopathies - From Basic Research to Clinical Management

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“…Later (24 h), mice were anesthetized (2-5% isoflurane), the chest was opened, and the heart was excised and immediately immersed in iced physiological saline solution (PSS; contents described below). The apical portion of the heart was carefully separated from the base using a scalpel, placed in formalin, and later prepared as appropriate to assess fibrosis and endothelial nitric oxide (NO) synthase (eNOS) immunostaining (see Histology) (8,12). Next, the coronary arteries were isolated from the base while it remained immersed in iced PSS and were used to measure reactivity (see Vascular function).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, gross histology showed that subendocardial fibrosis was more severe in hearts from CIRKO-TAC vs. WT-TAC mice. In the second study, 5 days of isoproterenol infusion produced similar LV hypertrophy between groups, but interstitial and subendocardial fibrosis was more pronounced in CIRKO mice (12). Third, adverse LV remodeling was accelerated in CIRKO hearts following coronary artery ligation (16).…”

mentioning

confidence: 88%

“…Hyperglycemia and altered insulin signaling may independently or collectively have negative consequences in the vasculature (3,5,14,21). In addition, growing evidence suggests that cardiac myocytes may affect the coronary vasculature through paracrine mechanisms (12).…”

mentioning

confidence: 99%

“…Previously, we examined the role of cardiomyocyte insulin signaling in left ventricular (LV) remodeling following LV pressure overload (8), isoproterenol infusion (12), and after coronary artery ligation (16). In the first investigation, the degree of LV hypertrophy evoked by 4 wk of transverse aortic constriction (TAC) was similar in CIRKO and wild-type (WT) mice, but a maladaptive pattern of LV remodeling was evident only in CIRKO animals (8).…”

mentioning

confidence: 99%

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Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload

Symons

Hu²,

Yang³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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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 cardiomyocyterestricted 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 Ͻ 0.05 vs. respective sham) in heart weight/body weight (mg/g) in WT-TAC (8.03 Ϯ 1.14, P Ͻ 0.05 vs. respective sham) and CIRKO-TAC (7.76 Ϯ 1.25, P Ͻ 0.05 vs. respective sham) vs. WT-sham (5.64 Ϯ 0.11) and CIRKO-sham (4.64 Ϯ 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 ϳ70% of maximal tension development using the thromboxane A2 receptor mimetic U-46619 (ϳ3 ϫ 10 Ϫ6 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 Ͻ 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. nitric oxide; blood vessel; mice; cardiac hypertrophy; endotheliumdependent vasorelaxation DIABETIC PATIENTS WITH CARDIOVASCULAR disease (CVD) have a worse prognosis than nondiabetic individuals who develop CVD (7). Even when the extent of coronary artery disease and infarct size are accounted for, diabetic patients have a higher incidence of heart failure and mortality in the setting of acute coronary syndromes or revascularization procedures. Although the precise mechanism responsible for the poor outcome of diabetic patients in these situations is unclear, insulin resistance and hyperglycemia may each play significant roles.Both cardiac myocytes and vascular endothelial cells may be adversely affected by diabetes, particularly in the setting of pathological stresses such as ischemia or pressure overload. Hyperglycemia and altered insulin signaling may independently or collectively have negative consequences in the vasculature (3,5,14,21). In addition, growing evidence suggests that cardiac myocytes may affect the coronary vasculature through paracrine mechanisms (12).To elucidate the ad...

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Role of the SHP2 Protein Tyrosine Phosphatase in Cardiac Metabolism

Kontaridis

Geladari

2013

Protein Tyrosine Phosphatase Control of Metabolism

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

Cited by 59 publications

References 33 publications

Insulin Resistance and Cardiomyopathy

Insulin Resistance and Cardiomyopathy

Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload

Role of the SHP2 Protein Tyrosine Phosphatase in Cardiac Metabolism

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