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

• 批准号: 10593096
• 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
• 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/10593096
• 关键词: Ablation; 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; absorption; aged; blood pressure reduction; cGMP-dependent protein kinase I; 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; mimetics; 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

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 高血压在美国是一个巨大的健康和社会经济负担，并且是高血压的主要原因。 全球心血管疾病发病率和死亡率。总的来说，三分之一的美国人患有高血压， 在65岁以上的美国人中，高血压会显著增加心脏病的风险 心力衰竭（HF），而降低血压可降低风险。据了解，高血压是最 射血分数保留性心力衰竭（HFpEF）发展的常见风险因素，其机制是 全身性炎症和活性氧的活化降低了一氧化氮的生物利用度， 蛋白激酶G（PKG）信号传导。慢性高血压的特征是收缩和舒张功能受损 心功能和病理性重塑，以及过度的肾钠潴留和容量超负荷， 共同导致进展为HFpEF和预后不良。试图减少血液的治疗 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， 对常规治疗有抵抗力，并且由于大多数HFpEF患者是老年人， 一氧化氮生物利用度和PKG信号传导的固有缺陷使得可用的疗法不太有效。 虽然，已知PKG信号传导受损是与高血压相关的心肾缺陷的中心 特别是在老年人中，专门设计用于增强PKG活性的疗法尚未成功。 我们的初步研究探索了一种替代方法来操纵PKG水平，以改善结果 在高血压和HFpEF中，通过绕过复杂的信号级联，有利于直接靶向 PKG的下游效应子。我们已经确定了一个磷酸化的丝氨酸残基273（S273）的调节 蛋白MyBPC作为PKG的关键特异性下游靶点，在各种压力模型中上调 超负荷诱导的高血压，但在HFpEF模型中下调。这些观察结果奠定了 这为我们的一般假设奠定了基础，即在慢性HTN中增加S273磷酸化水平可以防止 进展为HFpEF。在目的1中，我们将定义S273的PKG特异性体外分子机制 在目标2中，我们将利用高血压和HFpEF的实验模型和新的转基因动物。 动物模型，以确定改变的PKG水平和衰老的体内功能后果，目的3 我们将利用体内心脏选择性AAV9病毒基因递送磷酸化模拟物S273来预防或逆转心肌缺血。 老年小鼠和消融PKG小鼠中的HFpEF表型。成功完成这些机械化 研究有希望鉴定S273作为治疗高血压诱导的HFpEF的新治疗策略， 一种无法有效治疗的毁灭性疾病