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
基本信息
- 批准号:10035716
- 负责人:
- 金额:$ 66.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Action PotentialsAcute myocardial infarctionArrhythmiaAttenuatedAutonomic DysfunctionCarbacholCardiac MyocytesCardiovascular DiseasesCardiovascular systemCause of DeathCellsCoronary arteryCyclic AMP-Dependent Protein KinasesCyclic GMPCyclic GMP-Dependent Protein KinasesCytosolDangerousnessDataDevelopmentDiabetes MellitusDiastoleDietDisinhibitionEFRACEchocardiographyElectrocardiogramEpidemicFatty acid glycerol estersFunctional disorderGeneticGuanylate CyclaseHeartHeart ArrestHeart failureHomeostasisHumanHyperactive behaviorInsulinInsulin ResistanceKnockout MiceKnowledgeLeucine ZippersLifeLigationMeasurementMetabolic syndromeModelingMolecularMusMuscarinic AgonistsMuscle CellsMutant Strains MiceMyocardialMyocardial InfarctionNatriuretic PeptidesNon-Insulin-Dependent Diabetes MellitusPathogenesisPatientsPharmacologyPhosphodiesterase InhibitorsPhosphorylationPhosphotransferasesPhysiologicalPlacebosPlayPopulationPredispositionPrevention strategyProtein KinaseProteinsProtocols documentationPublishingRegulationRelaxationRoleSignal TransductionSignaling MoleculeSucroseSudden DeathSurfaceTechnologyTestingVentricularVentricular ArrhythmiaVentricular TachycardiaWestern BlottingbasecGMP Phosphodiesterase InhibitorcGMP-dependent protein kinase IcGMP-dependent protein kinase Ibetadb/db mousediabeticdiabetic patientexperimental studyglycogen synthase kinase 3 beta inhibitorheart rhythmhigh riskin vivoinhibitor/antagonistmortalitymouse modelmutantmutant mouse modelnovelnovel therapeuticsphosphodiesterase Vpreservationpreventresponsereuptakesildenafilsudden cardiac deathtau Proteinsuptake
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jonas Bernard Galper其他文献
Jonas Bernard Galper的其他文献
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{{ truncateString('Jonas Bernard Galper', 18)}}的其他基金
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:
10207769 - 财政年份:2020
- 资助金额:
$ 66.33万 - 项目类别:
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:
10443778 - 财政年份:2020
- 资助金额:
$ 66.33万 - 项目类别:
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:
10670741 - 财政年份:2020
- 资助金额:
$ 66.33万 - 项目类别:
Gender Specific Complications of Diabetic Autonomic Neuropathy: A New Mouse Model
糖尿病自主神经病变的性别特异性并发症:一种新的小鼠模型
- 批准号:
7923989 - 财政年份:2009
- 资助金额:
$ 66.33万 - 项目类别:
Gender Specific Complications of Diabetic Autonomic Neuropathy: A New Mouse Model
糖尿病自主神经病变的性别特异性并发症:一种新的小鼠模型
- 批准号:
7741155 - 财政年份:2009
- 资助金额:
$ 66.33万 - 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
- 批准号:
7316218 - 财政年份:2007
- 资助金额:
$ 66.33万 - 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
- 批准号:
7501466 - 财政年份:2007
- 资助金额:
$ 66.33万 - 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
- 批准号:
7911877 - 财政年份:2007
- 资助金额:
$ 66.33万 - 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
- 批准号:
7681627 - 财政年份:2007
- 资助金额:
$ 66.33万 - 项目类别:
Role of Sterols and Insulin in Cardiac Autonomic Response
甾醇和胰岛素在心脏自主反应中的作用
- 批准号:
8098062 - 财政年份:2004
- 资助金额:
$ 66.33万 - 项目类别:
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