Natriuretic Peptide System and Cardiac Fibrosis

本修订项目的广泛目标是建立cGMP激活因子作为新的和有效的慢性治疗策略，以减轻高血压性心脏病（HHD）心脏纤维化的发展。在这里，我们提出了针对颗粒鸟苷酸环化酶（pGC）的利钠肽（NP）和一种新的新化合物BAY 41-2272（BAY）的研究，该化合物直接靶向不依赖于一氧化氮（NO）的可溶性鸟苷酸环化酶（sGC）。我们还建议确定HHD患者抗纤维化cGMP治疗的心脏保护益处，这些益处超出常规治疗，除了改善心肌结构外，还可增强心肌功能。此外，我们还建议对NPs和BAY抑制心脏成纤维细胞（CF）增殖的机制进行新的研究，特别关注这些cGMP激活化合物抑制细胞周期的分子机制。 进展因此，项目2解决了所有创新项目的中心主题 心血管疾病的治疗策略。我们的具体目标和假设如下：目标1：确定与慢性噻嗪类利尿剂治疗相比，HHD患者慢性BNP或CBNP治疗的pGC激活的抗纤维化和心肌特性。假设：长期NP治疗在预防HHD患者心脏纤维化、抑制促纤维化因子激活、改善心室功能和增强心肌灌注方面上级噻嗪类利尿剂治疗。目标二：确定与慢性噻嗪类利尿剂治疗相比，慢性BAY治疗HHD患者慢性sGC激活的抗纤维化和心肌特性。假设：长期BAY治疗在预防HHD患者心脏纤维化、抑制促纤维化因子激活、改善心室功能和增强心肌灌注方面上级噻嗪类利尿剂治疗。目标3：在从正常和HHD心脏分离的CF中确定NP和BAY抑制CT-1和ET-1诱导的细胞周期进程的机制。假设：NP激活pGC或sGC激活 通过产生cGMP，BAY将降低细胞周期蛋白D1和E、Rb的磷酸化状态，并增加p16和p21蛋白，从而抑制进入细胞周期的S期。

The broad objective of this revised project is to establish cGMP-activating factors as novel and effective chronic therapeutic strategies to attenuate the development of cardiac fibrosis in hypertensive heart disease (HHD). Here we propose studies of the Natriuretic Peptides (NPs) that target particulate guanylyl cyclase (pGC) and a novel new compound BAY 41-2272 (BAY) that directly targets soluble guanylyl cyclase (sGC) independent of Nitric Oxide (NO). We also propose to define cardioprotective benefits of anti-fibrotic cGMP therapies in HHD that go beyond conventional therapies to enhance myocardial function in addition to improving myocardial structure. Further, we also propose to define new insights into the mechanisms by which the NPs and BAY inhibit cardiac fibroblast (CF) proliferation with a specific focus on molecular mechanisms whereby these cGMP-activating compounds inhibit cellcycle progression. Thus, Project 2 addresses the Central Theme of all projects that is innovative therapeutic strategies for cardiovascular disease. Our Specific Aims and Hypotheses are as follows: Aim 1: Determine the anti-fibrotic and myocardial properties of pGC activation with chronic BNP or CBNP therapy in HHD compared to chronic thiazide diuretic therapy. Hypothesis: Chronic NP therapy will be superior to thiazide diuretic therapy in preventing cardiac fibrosis, suppressing activation of profibrotic factors, improving ventricular function and enhancing myocardial perfusion in HHD. Aim 2: Determine the anti-fibrotic and myocardial properties of chronic sGC activation with chronic BAY therapy in HHD compared to chronic thiazide diuretic therapy. Hypothesis: Chronic BAY therapy will be superior to thiazide diuretic therapy in preventing cardiac fibrosis, suppressing activation of pro-fibrotic factors, improving ventricular function and enhancing myocardial perfusion in HHD. Aim 3: Determine in CFs isolated from normal and HHD hearts the mechanism(s) by which the NPs and BAY inhibit cell cycle progression induced by CT-1 and ET-1. Hypothesis: pGC activation by the NPs or sGC activation by BAY will, via cGMP production, decrease cyclin D1 and E, Rb phosphorylation status, and increase p16 and p21 proteins and thus inhibit entrance into the S-phase of the cell cycle.