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Novel downstream effectors of protein kinase G in hypertensive disease

高血压疾病中蛋白激酶 G 的新型下游效应子

基本信息

批准号：
10228381
负责人：
Julian Stelzer
金额：
$ 62.22万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10228381
关键词：
Address Aging American Animal Model Aortic Valve Stenosis Biological Availability Bypass Cardiac Cardiovascular system Chronic Chronic stress Clinical Clinical Trials Complex Conscious Cyclic AMP-Dependent Protein Kinases Cyclic GMP-Dependent Protein Kinases Death Rate Dependovirus Development Disease EFRAC Economic Burden Experimental Models Failure Foundations Functional disorder Gene Delivery Gene Transfer Generations Genetically Engineered Mouse Genomics Heart Heart failure Hypertension Impairment In Vitro Incidence Individual Kidney Left Left Ventricular Dysfunction Measurement Measures Medical Modeling Molecular Morbidity - disease rate Mus Muscle Mutation Myocardial dysfunction Myocardium Nephrons Nitric Oxide Organ Outcome Oxidative Stress Pathologic Patients Phenotype Phosphorylation Prevalence Prevention Prognosis Property Reactive Oxygen Species Regulation Relaxation Renal function Resistance Risk Risk Factors Serine Signal Pathway Signal Transduction Sodium Stress Testing Transgenic Animals Transgenic Mice United States Ventricular Ventricular Remodeling aged blood pressure reduction cGMP-dependent protein kinase I cardiogenesis cardioprotection cardiovascular risk factor conventional therapy design effective therapy genetic regulatory protein health economics heart function human old age (65+)improved improved outcome in vivo kidney dysfunction mortality new therapeutic target normotensive novel novel therapeutic intervention novel therapeutics older patient preservation pressure prevent renal damage response side effect socioeconomics success systemic inflammatory response therapy development tool translational study viral gene delivery

项目摘要

Abstract Hypertension is an enormous health and socio-economic burden in the United States and is a leading cause of cardiovascular morbidity and mortality worldwide. Overall, 1 in 3 of Americans have hypertension, and nearly 2 in 3 of Americans over the age of 65 years. Hypertension significantly increases the risk of developing heart failure (HF), whereas reducing blood pressure decreases the risk. It is known that hypertension is the most common risk factor in the development of HF with preserved ejection fraction (HFpEF) by a mechanism where systemic inflammation and activation of reactive oxygen species reduces nitric oxide bioavailability and impairs Protein kinase G (PKG) signaling. Chronic hypertension is characterized by impaired systolic and diastolic cardiac function and pathological remodeling, and excessive renal sodium retention and volume overload, which together contribute to progression to HFpEF and a poor prognosis. Therapies attempting to reduce blood pressure in HFpEF patients have mostly failed to yield positive results. Many patients have hypertension that is resistant to conventional therapy, and because the majority of HFpEF patients are elderly, they display aging inherent deficits in nitric oxide bioavailability and PKG signaling that make available therapies less effective. Although, it is known that impaired PKG signaling is central to the cardio-renal deficits related to hypertension especially in older individuals, therapies specifically designed to enhance PKG activity have not been successful. Our preliminary studies have explored an alternative approach to manipulating PKG levels to improve outcomes in hypertension and HFpEF by bypassing complex signaling cascades in favor of directly targeting the downstream effectors of PKG. We have identified a phosphorylatable serine residue 273 (S273) in the regulatory protein MyBPC as a critical specific downstream target of PKG that is upregulated in various models of pressure overload-induced hypertension, but is downregulated in models of HFpEF. These observations lay the foundation for our general hypothesis that increasing S273 phosphorylation levels in chronic Htn prevents progression to HFpEF. In Aim 1 we will define the PKG-specific in vitro molecular mechanisms of S273 phosphorylation, in Aim 2 we will utilize experimental models of hypertension and HFpEF and novel transgenic animal models to determine the in vivo functional consequences of altered PKG levels and aging, and in Aim 3 we will utilize in vivo cardioselective AAV9 viral gene delivery of phosphomimetic S273 to prevent or reverse the HFpEF phenotype in aged mice and in mice with ablated PKG. Successful completion of these mechanistic studies have the promise to identify S273 as a novel therapeutic strategy to treat hypertension-induced HFpEF, a devastating disease with no effective treatments.

摘要