Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness

Bergh, An Van Den; Vanderper, Annelies; Vangheluwe, Peter; Desjardins, Fanny; Nevelsteen, Ines; Verreth, Wim; Wuytack, Frank; Holvoet, Paul; Flameng, Willem; Balligand, Jean‐Luc; Herijgers, Paul

doi:10.1093/cvr/cvm001

Cited by 72 publications

(92 citation statements)

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“…LVDD but not systolic dysfunction was associated with increased cardiac triglyceride content in ob/ob mice [24]. Furthermore, these mice also exhibit impaired calcium reuptake that was associated with LV contractile dysfunction [25,26]. Impaired contractility in cardiomyocytes isolated from sedentary db/db mice was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca 2+ leak, reduced synchrony of Ca 2+ release, lower peak systolic and diastolic Ca 2+ and caffeine-induced Ca 2+ release, consistent with a role for calcium in the LVDD seen in type 2 DM [27].…”

Section: Discussionmentioning

confidence: 99%

Left ventricular diastolic dysfunction in normotensive postmenopausal women with type 2 diabetes mellitus

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Left ventricular diastolic dysfunction in normotensive postmenopausal women with type 2 diabetes mellitus

et al. 2017

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“…Measurements (see Methods in the online-only Data Supplement for details) were performed by the same operator, blinded to the experimental groups, before and after the hypertrophy protocol in each mouse. In vivo cardiac performance was measured by both load-dependent and load-independent parameters derived from pressure-volume (P-V) loops using miniaturized pressure-conductance catheters 22 in mice anesthetized with a mixture of urethane (1200 mg/kg)-α-chloralose (50 mg/kg), as described in the Methods in the online-only Data Supplement. stained with picrosirius red for interstitial collagen volume fraction quantification, Isolectin B4 for endothelial cells and capillary density, and wheat germ agglutinin for cardiac myocyte measurements.…”

Section: Echocardiographic and Hemodynamic Measurementsmentioning

confidence: 99%

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

et al. 2014

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451H emodynamic overload and ischemic or oxidative stress promote adverse cardiac remodeling, a leading cause of worsening heart failure.1,2 Most of these pathophysiologic conditions are associated with (and to a certain extent, mediated by) adrenergic stimulation and catecholamines release, resulting in adrenoceptor (AR) activation on different cell types within the myocardium. Among these, cardiac myocyte β1-ARs are classically considered to mediate short-term positive effects on all aspects of myocardial contractility; however, long-term stimulation produces adverse effects on myocardial remodeling, in part through activation of calciumdependent prohypertrophic effects, ultimately associated with cardiomyocyte loss. 3,4 Such maladaptive remodeling is usually accompanied by left ventricle (LV) geometry disruption Background-β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. Methods and Results-Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1.Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. Conclusions-Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling. and interstitial and replacement fibrosis leading to progressive diastolic and systolic heart failure. Deciphering the underlying signaling pathways may lead to new therapeutic strategies that favorably modulate remodeling. The use of β1-AR blockers provided a major advance in this direction, albeit far from totally efficient. 5 The third isotype of β-AR (β3-AR) has classically been considered as a metabolic regulator (eg, by mediating lipolysis in the adipose tissue).6 β3-ARs ...

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“…ob/ob cardiomyocytes have an increased malondialdehyde content, reduced GSH/GSSG ratios, increased protein carbonyl formation, and increased levels of the p47 and gp91 subunits of NADPH oxidase, suggesting that oxidative stress occurs in ob/ob hearts , and decreased SERCA2a activity . Ca 2+ transients are smaller and slower, and sarcoplasmic reticulum (SR) Ca 2+ reuptake is impaired (Fauconnier et al, 2005;Van den Bergh et al, 2008). Apoptotic cell death and caspase 3 activity are also increased in ob/ob hearts (Barouch et al, 2006;Van den Bergh et al, 2008).…”

Section: Disease Models and Mechanisms Dmmmentioning

confidence: 99%

“…Ca 2+ transients are smaller and slower, and sarcoplasmic reticulum (SR) Ca 2+ reuptake is impaired (Fauconnier et al, 2005;Van den Bergh et al, 2008). Apoptotic cell death and caspase 3 activity are also increased in ob/ob hearts (Barouch et al, 2006;Van den Bergh et al, 2008).…”

Section: Disease Models and Mechanisms Dmmmentioning

confidence: 99%

Rodent models of diabetic cardiomyopathy

Bugger

Abel

2009

Disease Models &Amp; Mechanisms

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Diabetic cardiomyopathy increases the risk of heart failure in individuals with diabetes, independently of co-existing coronary artery disease and hypertension. The underlying mechanisms for this cardiac complication are incompletely understood. Research on rodent models of type 1 and type 2 diabetes, and the use of genetic engineering techniques in mice, have greatly advanced our understanding of the molecular mechanisms responsible for human diabetic cardiomyopathy. The adaptation of experimental techniques for the investigation of cardiac physiology in mice now allows comprehensive characterization of these models. The focus of the present review will be to discuss selected rodent models that have proven to be useful in studying the underlying mechanisms of human diabetic cardiomyopathy, and to provide an overview of the characteristics of these models for the growing number of investigators who seek to understand the pathology of diabetes-related heart disease.

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Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness

Abstract: Type II diabetes in mice leads to impaired contractility and relaxation due to disturbed Ca(2+) reuptake in the SR, but only when dyslipidaemia and hypertension are superimposed does vascular-ventricular stiffening increase and left ventricular myocardial fibrosis develop.

Cited by 72 publications

References 29 publications

Left ventricular diastolic dysfunction in normotensive postmenopausal women with type 2 diabetes mellitus

Left ventricular diastolic dysfunction in normotensive postmenopausal women with type 2 diabetes mellitus

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Rodent models of diabetic cardiomyopathy

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