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Inhibiting Insulin-Mediated ?2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction.

ABSTRACT: Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity.High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking ?2-adrenergic receptor (?2AR) or ?-arrestin2. Wild-type mice fed with high-fat diet were treated with a ?-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function.High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and ?-arrestin2-dependent transactivation of a ?2AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of ?2AR or GRK2, or genetic deletion of ?2AR or ?-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction.These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify ?2AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.

SUBMITTER: Wang Q

PROVIDER: S-EPMC5302024 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Inhibiting Insulin-Mediated β2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction.

Wang Qingtong Q Liu Yongming Y Fu Qin Q Xu Bing B Zhang Yuan Y Kim Sungjin S Tan Ruensern R Barbagallo Federica F West Toni T Anderson Ethan E Wei Wei W Abel E Dale ED Xiang Yang K YK

Circulation 20161104 1

<h4>Background</h4>Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity.<h4>Methods</h4>High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with ...[more]

PMID: 27815373

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Project description:Obesity rates have rapidly increased worldwide and obesity-related diseases such as hypertension and cardiovascular diseases have become leading factors for global morbidity and mortality. Currently, there are no effective treatments that can prevent or reverse obesity long-term, and hence the prevention of obesity-related adverse effects such as hypertension is critical. Qingda granule (QDG) is a condensed Traditional Chinese Medicine (TCM) formula that has been used clinically for treating hypertension, however, its effectiveness in obesity-induced hypertension and cardiac dysfunction remains explored. Mouse models of obesity via long-term feeding of high-fat high-fructose diet (HFFD) were established to examine the effect and mechanism of QDG in protecting against obesity-induced hypertension and cardiac dysfunction. C57BL/6 mice were fed with either normal diet or HFFD over a period of 16 weeks and administered with either saline or QDG for assessment of obesity-induced blood pressure and cardiac function. QDG administration demonstrated robust anti-hypertensive effects and significantly attenuated HFFD-induced elevations in blood pressures. Moreover, QDG treatment also demonstrated robust cardioprotective effects during obesity-induced hypertension by markedly improving cardiac function and preventing cardiac hypertrophy. QDG protected against obesity-induced hypertension and cardiac dysfunction was due to its ability to prevent adverse chronic activation of Akt signaling pathway during long-term feeding of HFFD. Long-term usage of QDG treatments exhibited no observable side effects and also completely prevented obesity-induced organ damage, demonstrating the feasibility and safety of prolonged use. Our findings thus elucidated the role of QDG in preventing obesity-induced hypertension and cardiac hypertrophy via inhibiting adverse activation of Akt signaling activation. Therefore, our study provides the theoretical basis for the utilization of QDG as both a safe and effective drug in the therapeutic treatment of metabolic diseases such as obesity-induced hypertension.

Project description:In order to determine the role of the adrenergic system in bupivacaine-induced cardiotoxicity, a series of experiments were performed. In an animal experiment, male Sprague-Dawley (SD) rats under chloral hydrate anesthesia received intravenous bupivacaine, followed by an intravenous injection of adrenalin or isoprenalin, and the electrocardiogram (ECG), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximum rate of rise of left ventricular pressure (+dP/dtmax) and the maximum rate of pressure decrease (-dP/dtmax) were continually monitored. In a cellular experiment, freshly isolated adult SD rat ventricular myocytes were perfused with bupivacaine at different concentrations in the presence or absence of isoprenalin, with or without esmolol. The percentage of the sarcomere shortening (bl% peak h), departure velocity (dep v) of sarcomere shortening and time to 50% of the peak speed of myocyte contraction (Tp50) was assessed by a video-based edge-detection system. In an additional experiment, Swiss mice pretreated with saline, isoprenalin, esmolol or dexmedetomidine received bupivacaine to determine the 50% lethal dose (LD50) of bupivacaine. Electron microscopy of myocardial mitochondria was performed to assess damage of these structures. To test mitochondrial reactive oxygen species (ROS) production, freshly isolated SD rat ventricular myocytes were incubated with bupivacaine in the presence of isoprenalin, with or without esmolol. First, our results showed that bupivacaine significantly reduced the LVSP and +dP/dtmax, as well as enhanced the LVEDP and -dP/dtmax (P < 0.05, vs. control, and vs. baseline). Adrenalin and isoprenalin induced a further reduction of LVSP and +dP/dtmax (P < 0.05, vs. before adrenalin or isoprenalin delivery, and vs. control). Second, bupivacaine induced a dose-dependent cardiomyocyte contractile depression. While 5.9 μmol/L or 8.9 μmol/L of bupivacaine resulted in no change, 30.0 μmol/L of bupivacaine prolonged the Tp50 and reduced the bl% peak h and dep v (P < 0.05, vs. control and vs. baseline). Isoprenalin aggravated the bupivacaine-induced cardiomyocyte contractile depression, significantly prolonging the Tp50 (P < 0.05, vs. bupivacaine alone) and reducing the dep v (P < 0.05, vs. bupivacaine alone). Third, esmolol and dexmedetomidine significantly enhanced, while isoprenalin significantly reduced, the LD50 of bupivacaine in mice. Fourth, bupivacaine led to significant mitochondrial swelling, and the extent of myocardial mitochondrial swelling in isoprenalin-pretreated mice was significantly higher than that compared with mice pretreated with saline, as reflected by the higher mitochondrial damage score (P < 0.01). Meanwhile, esmolol pretreatment significantly reduced the mitochondrial damage score (P < 0.01). Fifth, bupivacaine significantly increased the ROS in freshly isolated cardiomyocytes, and added isoprenalin induced a further enhancement of ROS production (P < 0.05, vs. bupivacaine alone). Added esmolol significantly decreased ROS production (P < 0.05, vs. bupivacaine + isoprenalin). Our results suggest that bupivacaine depressed cardiac automaticity, conductivity and contractility, but the predominant effect was contractile dysfunction which resulted from the disruption of mitochondrial energy metabolism. β-adrenergic activation aggravated the cellular metabolism disorder and therefore contractile dysfunction.

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Inhibiting Insulin-Mediated ?2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction.

Publications

Inhibiting Insulin-Mediated β2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction.

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