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Loss of myocardial retinoic acid receptor ? induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.

ABSTRACT: Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RAR? signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RAR? deletion (RAR?KO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RAR?KO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RAR?KO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RAR?KO mouse hearts, which were rescued by overexpression of RAR? in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II ? (CaMKII ?) was observed in RAR?KO mouse hearts. Ca2+ reuptake and cardiomyocyte relaxation were delayed by RAR? deletion. Overexpression of RAR? or inhibition of ROS generation or NOX activation prevented RAR? deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+ reuptake. Moreover, the gene and protein expression of RAR? was significantly decreased in aged or metabolic stressed mouse hearts. RAR? deletion accelerated the development of diastolic dysfunction in streptozotocin (STZ)-induced type 1 diabetic mice or in high fat diet fed mice. In conclusion, myocardial RAR? deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca2+ mishandling in RAR?KO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RAR? signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction.

SUBMITTER: Zhu S

PROVIDER: S-EPMC5107335 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.

Zhu Sen S Guleria Rakeshwar S RS Thomas Candice M CM Roth Amanda A Gerilechaogetu Fnu F Kumar Rajesh R Dostal David E DE Baker Kenneth M KM Pan Jing J

Journal of molecular and cellular cardiology 20160815

Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16wks of gene deletion. However, no significant differences were observed ...[more]

PMID: 27539860

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Project description:Insulin resistance is associated with obesity and may be accompanied by left ventricular diastolic dysfunction and myocardial remodeling. Decreased insulin metabolic signaling and increased oxidative stress may promote these maladaptive changes. In this context, the beta-blocker nebivolol has been reported to improve insulin sensitivity, increase endothelial NO synthase activity, and reduce NADPH oxidase-induced superoxide generation. We hypothesized that nebivolol would attenuate diastolic dysfunction and myocardial remodeling by blunting myocardial oxidant stress and promoting insulin metabolic signaling in a rodent model of obesity, insulin resistance, and hypertension. Six-week-old male Zucker obese and age-matched Zucker lean rats were treated with nebivolol (10 mg x kg(-) x day(-1)) for 21 days, and myocardial function was assessed by cine MRI. Compared with untreated Zucker lean rats, untreated Zucker obese rats exhibited prolonged diastolic relaxation time (27.7+/-2.5 versus 40.9+/-2.0 ms; P<0.05) and reduced initial diastolic filling rate (6.2+/-0.5 versus 2.8+/-0.6 microL/ms; P<0.05) in conjunction with increased homeostatic model assessment of insulin resistance (7+/-2 versus 95+/-21; P<0.05), interstitial and pericapillary fibrosis, abnormal cardiomyocyte histoarchitecture, 3-nitrotyrosine, and NADPH oxidase-dependent superoxide. Nebivolol improved diastolic relaxation (32.8+/-0.7 ms; P<0.05 versus untreated Zucker obese), reduced fibrosis, and remodeling in Zucker obese rats, in concert with reductions in nitrotyrosine, NADPH oxidase-dependent superoxide, and improvements in the insulin metabolic signaling, endothelial NO synthase activation, and weight gain (381+/-7 versus 338+/-14 g; P<0.05). Results support the hypothesis that nebivolol reduces myocardial structural maladaptive changes and improves diastolic relaxation in concert with improvements in insulin sensitivity and endothelial NO synthase activation, concomitantly with reductions in oxidative stress.

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Dataset Information

Loss of myocardial retinoic acid receptor ? induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.

Publications

Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.

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