A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome

PKG1a 和 cGMP 磷酸二酯酶抑制剂在 II 型糖尿病和代谢综合征小鼠模型 MI 后 VT 中的作用

• 批准号: 10035716
• 负责人: Jonas Bernard Galper
• 金额: $ 66.33万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10035716
• 关键词: Action Potentials; Acute myocardial infarction; Arrhythmia; Attenuated; Autonomic Dysfunction; Carbachol; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Coronary artery; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cytosol; Dangerousness; Data; Development; Diabetes Mellitus; Diastole; Diet; Disinhibition; EFRAC; Echocardiography; Electrocardiogram; Epidemic; Fatty acid glycerol esters; Functional disorder; Genetic; Guanylate Cyclase; Heart; Heart Arrest; Heart failure; Homeostasis; Human; Hyperactive behavior; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Leucine Zippers; Life; Ligation; Measurement; Metabolic syndrome; Modeling; Molecular; Mus; Muscarinic Agonists; Muscle Cells; Mutant Strains Mice; Myocardial; Myocardial Infarction; Natriuretic Peptides; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Patients; Pharmacology; Phosphodiesterase Inhibitors; Phosphorylation; Phosphotransferases; Physiological; Placebos; Play; Population; Predisposition; Prevention strategy; Protein Kinase; Proteins; Protocols documentation; Publishing; Regulation; Relaxation; Role; Signal Transduction; Signaling Molecule; Sucrose; Sudden Death; Surface; Technology; Testing; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; Western Blotting; base; cGMP Phosphodiesterase Inhibitor; cGMP-dependent protein kinase I; cGMP-dependent protein kinase Ibeta; db/db mouse; diabetic; diabetic patient; experimental study; glycogen synthase kinase 3 beta inhibitor; heart rhythm; high risk; in vivo; inhibitor/antagonist; mortality; mouse model; mutant; mutant mouse model; novel; novel therapeutics; phosphodiesterase V; preservation; prevent; response; reuptake; sildenafil; sudden cardiac death; tau Proteins; uptake

Project Summary The current application proposes to investigate the novel mechanisms through which cGMP and the cGMP- dependent protein kinase I (PKGI) maintain Ca homeostasis and oppose ventricular tachycardia (VT) in the diabetic heart in the setting of acute MI. Diabetes mellitus (DM) is associated with an increase in sudden cardiac death (SCD), but the molecular and cellular mechanisms of arrhythmogenesis in DM remain incompletely understood. T-Wave alternans (TWA) is a rate dependent beat-to-beat fluctuation on the surface EKG that has been associated with life threatening ventricular arrhythmias. T-wave alternans has been described in patients with Type II DM, and hyperactivity of GSK3β has been implicated in secondary effects of DMII, but little is known regarding the mechanism of alternans and its specific role in the pathogenesis of VT in patients, or in mouse models for Type II DM. Inducibility of VT in response to programmed ventricular stimulation has been used to identify patients whose hearts are predisposed to the development of VT. Preliminary data in the current application identify significant inducibility of VT and of TWA in two separate models: the Db/Db mouse model of DMII, and in the High Fat High Sucrose (HFHS) fed mouse model of insulin insensitivity. More importantly, we have demonstrated that these mice develop severe spontaneous arrhythmias following myocardial infarction (MI). We have observed that the intracellular signaling molecule cGMP is decreased in both of these above models. Further, genetic disruption of the primary cardiovascular cGMP effector, Protein Kinase G Iα (PKGIα) leads to T-wave alternans and highly inducible VT, providing direct evidence that this kinase plays a role in the pathogenesis of VT in vivo. Rescue experiments demonstrate that augmentation of cGMP with the cGMP- selective phosphodiesterase 5 inhibitor sildenafil abolishes VT and TWA in the Db/Db and HFHS mice, while the GSK3β inhibitor TWS-119 attenuates VT. Based on these and published data implicating GSK3β as a PKG1α substrate, the current application proposes to test the hypothesis that PKGIα opposes both inducible and spontaneous post MI VT in the diabetic heart through the regulation of GSK3β activity. We propose 3 Specific Aims: 1) Determine the anti-arrhythmic effects of PKGI augmentation in the DMII heart by PDE inhibitors and Guanylate cyclase activators; 2) Determine the physiologic mechanisms by which PKGIα dysfunction predisposes to inducible and post MI VT and alternans via an effect on Ca homeostasis; 3) Determine the downstream signaling mechanisms through which disruption of cGMP-PKG signaling promotes VT in the DMII heart. The data generated from these studies will determine the role of PKGIα signaling in the regulation of VT in the DM II heart and has the potential to identify pharmacologic modulation of PKGI as a novel anti-arrhythmic strategy in patients with DM.

项目总结