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：
10380140
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/10380140
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+)hypertensive 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.

抽象的高血压是美国的巨大健康和社会经济负担，是全球心血管发病率和死亡率。总体而言，三分之一的美国人患有高血压，近2人在65岁以上的美国人中有3名。高血压大大增加了心脏发展的风险失败（HF），而降低血压会降低风险。众所周知，高血压是最大的通过保留的射血分数（HFPEF）的HF开发的常见危险因素，该机制在其中全身性炎症和活性氧的激活减少一氧化氮的生物利用度并损害蛋白激酶G（PKG）信号传导。慢性高血压的特征是收缩和舒张期受损心脏功能和病理重塑，以及过多的肾钠保留和体积超负荷，共同有助于向HFPEF发展和预后不佳。试图减少血液的疗法 HFPEF患者的压力大多未能产生阳性结果。许多患者患有高血压对常规疗法有抵抗力，并且由于大多数HFPEF患者是老年人，因此它们显示出衰老一氧化氮生物利用度和PKG信号传导的固有缺陷，可提供疗效的效果降低。虽然，众所周知，PKG信号受损是与高血压有关的心脏肾脏缺陷的核心特别是在老年人中，专门设计用于增强PKG活动的疗法尚未成功。我们的初步研究探索了一种操纵PKG水平以改善预后的替代方法在高血压和HFPEF中，通过绕过复合信号级联反应直接针对 PKG的下游效应子。我们已经确定了调节性的可磷酸化丝氨酸残基273（S273）蛋白MYBPC是PKG的关键特异性下游目标，在各种压力模型中被上调超载引起的高血压，但在HFPEF模型中被下调。这些观察结果是我们的一般假设的基础，即慢性HTN的S273磷酸化水平增加向HFPEF发展。在AIM 1中，我们将定义S273的PKG特异性分子机制磷酸化，在AIM 2中，我们将利用高血压和HFPEF的实验模型以及新型转基因动物模型以确定PKG水平和衰老改变的体内功能后果，以及AIM 3 我们将利用体内辅导性AAV9病毒基因递送磷酸化S273的递送来预防或逆转老年小鼠和带有消融PKG的小鼠中的HFPEF表型。这些机械的成功完成研究有望将S273识别为一种治疗高血压诱导的HFPEF的新型治疗策略，没有有效治疗的毁灭性疾病。