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: 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
• 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

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 高血压是美国巨大的健康和社会经济负担，也是导致高血压的主要原因 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 3 名 65 岁以上的美国人。高血压显着增加患心脏病的风险 失败（HF），而降低血压则降低风险。据了解，高血压是最 射血分数保留型心力衰竭 (HFpEF) 发生的常见危险因素，其机制如下： 全身炎症和活性氧的激活会降低一氧化氮的生物利用度并损害 蛋白激酶 G (PKG) 信号传导。慢性高血压的特点是收缩压和舒张压受损 心脏功能和病理重塑，以及肾钠潴留和容量超负荷过多， 共同导致 HFpEF 进展和不良预后。试图减少血液的疗法 HFpEF 患者的压力大多未能产生积极的结果。很多患者都患有高血压， 对常规治疗有抵抗力，并且由于大多数 HFpEF 患者都是老年人，因此他们表现出衰老 一氧化氮生物利用度和 PKG 信号传导的固有缺陷导致现有疗法效果较差。 尽管如此，众所周知，PKG 信号传导受损是与高血压相关的心肾功能不全的核心 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操纵 PKG 水平以改善结果的替代方法 通过绕过复杂的信号级联，有利于直接靶向高血压和 HFpEF PKG 的下游效应子。我们在监管中发现了一个可磷酸化的丝氨酸残基 273 (S273) 蛋白质 MyBPC 作为 PKG 的关键特定下游靶标，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。这些观察奠定了 我们一般假设的基础是增加慢性 Htn 中的 S273 磷酸化水平可以预防 进展为 HFpEF。在目标 1 中，我们将定义 S273 的 PKG 特异性体外分子机制 磷酸化，在目标 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 水平改变和衰老的体内功能后果，以及目标 3 我们将利用磷模拟 S273 的体内心脏选择性 AAV9 病毒基因传递来预防或逆转 老年小鼠和 PKG 消融小鼠的 HFpEF 表型。顺利完成这些机械 研究有望将 S273 确定为治疗高血压引起的 HFpEF 的新治疗策略， 一种没有有效治疗方法的毁灭性疾病。