Role and Mechanisms of cGMP-PDE Compartmentation in Cardiac Stress

cGMP-PDE 区室在心脏应激中的作用和机制

• 批准号: 9189461
• 负责人: Kristen Kokkonen-Simon
• 金额: $ 4.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2019-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189461
• 关键词: Address; Affect; Angiotensin Receptor; Animals; Attenuated; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Catabolism; Categories; Cause of Death; Cells; Clinical Trials; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Dependence; Diagnosis; Disease; Drug Targeting; EFRAC; Economics; Electron Microscopy; Enalapril; Enzymes; Erectile dysfunction; Estrogens; Female; Gene Deletion; Genetic; Gonadal Steroid Hormones; Guanylate Cyclase; Health Care Costs; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hormones; Human; Ischemia; Knockout Mice; Link; Mental Depression; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Natriuretic Peptides; Neprilysin; Nitric Oxide; Pathway interactions; Patients; Peptide Receptor; Pharmaceutical Preparations; Phosphodiesterase Inhibitors; Play; Postmenopause; Protein Isoforms; Proteome; Pulmonary Hypertension; Regulation; Rodent; Role; Signal Pathway; Signal Transduction; Soluble Guanylate Cyclase; Specificity; Stress; Testing; Therapeutic; Treatment Efficacy; United States; Woman; abstracting; base; effective therapy; falls; gene synthesis; heart function; improved; in vivo; inhibitor/antagonist; interest; male; next generation sequencing; novel; phosphoric diester hydrolase; pressure; receptor coupling; sex; stressor; tool; transcriptome

Abstract Heart failure (HF) is a leading cause of death globally, affecting almost 6 million people in the United States alone. Up to 50% of these patients will die within five years of diagnosis, making elucidation of the mechanistic underpinnings imperative so they can be evaluated for therapeutic potential. Evidence from our lab has shown that phosphodiesterases (PDEs) that degrade cyclic guanosine monophosphate (cGMP) have great utility as druggable targets in heart failure. These PDEs ultimately block protein kinase G (PKG) signaling, a known cardioprotective pathway; hence blockade of PDE activity results in cardioprotection. Several cGMP-specific PDEs are present in the heart, namely the nitric oxide-linked PDE5a and the natriuretic peptide-linked PDE9a. These PDEs are compartmentalized to specific regions of the cell, although little is known about this compartmentation for PDE5, and nothing is known for PDE9. Part of this proposal aims to study this compartmentation using novel molecular tools such as compartment-targeted PKG inhibitors and tagged PDEs that can be used to determine subcellular localization and compartment-specific proteomes. Knowing the specifics of the PDE5 and PDE9 compartments may clarify how these PDEs can be manipulated for therapeutics. Previous in vivo studies have demonstrated that inhibition of PDE5 has great therapeutic utility in male animal HF models, but has fallen short in female mice lacking estrogen (comparable to HF in postmenopausal women) and in human HF with preserved ejection fraction patients. These shortcomings are due to the regulation of nitric oxide by estrogen and the depression of nitric oxide levels in HF, respectively. Recently we revealed that inhibition or genetic deletion of PDE9a, the other cGMP-specific PDE in the heart, attenuates cardiac hypertrophy in male mice. The PDE9 pathway acts independently of the nitric oxide/PDE5 pathway, making it a promising drug target in situations where PDE5 inhibition is ineffective. We hypothesize that inhibition of PDE9 will result in improved cardiac function in rodent pressure-overload models independent of sex and sex hormone status. This hypothesis will be tested in a female pressure-overload HF model using C57Bl6 mice treated with PDE9 inhibitors and PDE9a knockout mice lacking estrogen.

摘要 心力衰竭（HF）是全球死亡的主要原因，影响美国近600万人。 只有国家。高达50%的这些患者将在诊断后五年内死亡，这说明 机械基础是必要的，因此可以评估它们的治疗潜力。 我们实验室的证据表明，降解环鸟苷的磷酸二酯酶（PDE） cGMP作为心力衰竭的药物靶点具有很大的实用性。这些PDE 最终阻断蛋白激酶G（PKG）信号传导，这是一种已知的心脏保护途径; PDE活性的降低导致心脏保护。几种cGMP特异性PDE存在于心脏中， 即一氧化氮连接的PDE 5a和利钠肽连接的PDE 9a。这些PDE是 分隔到细胞的特定区域，尽管对这种分隔知之甚少 对于PDE 5，没有什么是已知的PDE 9。本提案的一部分旨在研究这种划分 使用新的分子工具，如隔室靶向PKG抑制剂和标记的PDE， 可用于确定亚细胞定位和区室特异性蛋白质组。知道 PDE 5和PDE 9区室的细节可以阐明如何操纵这些PDE， 治疗学先前的体内研究已经证明，PDE 5的抑制具有很大的生物学活性。 在雄性动物HF模型中的治疗效用，但在缺乏雌激素的雌性小鼠中的治疗效用不足 （与绝经后女性HF相当）和射血分数保留的人HF 患者这些缺点是由于雌激素和抑郁症对一氧化氮的调节 HF中的一氧化氮水平。最近，我们发现，抑制或基因删除， PDE 9a是心脏中的另一种cGMP特异性PDE，可减弱雄性小鼠的心脏肥大。的 PDE 9通路独立于一氧化氮/PDE 5通路发挥作用，使其成为一种有前途的药物 在PDE 5抑制无效的情况下靶向。我们假设抑制PDE 9将 在啮齿动物压力超负荷模型中改善心脏功能，与性别和性别无关 激素状态将使用C57 B16在女性压力超负荷HF模型中检验该假设 用PDE 9抑制剂处理的小鼠和缺乏雌激素的PDE 9a敲除小鼠。