Ac-SDKP in target organ damage in hypertension

Ac-SDKP 在高血压靶器官损伤中的作用

• 批准号: 6649484
• 负责人: Oscar A. Carretero
• 金额: $ 7.35万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649484
• 关键词: ACE inhibitors; aldosterone; angiotensin II; antiinflammatory agents; cell growth regulation; cell proliferation; collagen; cytokine; cytoprotection; fibrogenesis; fibrosis; gene deletion mutation; genetically modified animals; growth inhibitors; heart function; hypertension; inflammation; kinins; laboratory mouse; laboratory rat; myocardial infarction; nitric oxide; oligopeptides; oxidative stress; protein biosynthesis; protein degradation

DESCRIPTION: (provided by applicant) Hypertension is a cardiovascular risk factor that often leads to target organ damage. Angiotensin-converting enzyme inhibitors (ACEi) significantly reduce cardiovascular events, especially in high-risk patients. The effects of ACEi are mediated by inhibition of both the conversion of Ang I to Ang II and kinin degradation. We have evidence that in hypertension another peptide hydrolyzed by ACE, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), prevents and reverses cardiac fibrosis without altering blood pressure (BP) or cardiocyte hypertrophy. This is the first demonstration that administration of Ac-SDKP has an effect on cardiac fibrosis; however, we do not know whether Ac-SDKP has a physiological role, the mechanism by which it inhibits fibrosis or whether it contributes to the cardiovascular protective effects of ACEi. In this project we propose to test the general hypothesis that in hypertension cardiac fibrosis is the result of an alteration of the balance between pro-fibrotic and pro-inflammatory vs anti-fibrotic and anti-inflammatory systems. Ac-SDKP alters this balance in favor of the latter, reversing fibrosis (an important component of target organ damage) and improving cardiac function. The mechanisms by which Ac-SDKP antagonizes pro-fibrotic stimuli are: a) directly by inhibiting fibroblast proliferation and collagen synthesis and b) indirectly by acting as an anti-inflammatory cytokine, thus inhibiting production of TGF beta 1 and other cytokines and macrophage activation and infiltration. We also hypothesize that part of the anti-fibrotic effect of ACEi on target organ damage is mediated by Ac-SDKP interacting synergistically with kinins and NO. To test this hypothesis, we propose to conduct in vivo studies, using a combination of physiological, pharmacological and molecular approaches (gene deletion). In the first two aims we will determine the mechanisms by which Ac-SDKP prevents and reverses cardiac fibrosis. In Aim 1 we will study its effect on fibroblast proliferation and collagen synthesis and degradation. In Aim 2 we will study whether Ac-SDKP inhibits cardiac fibrosis in part by acting as an anti-inflammatory cytokine, decreasing proinflammatory cytokines and macrophage activation and infiltration and reactive oxygen species production. In Aim 3, we will study whether in hypertension Ac- SDKP improves diastolic dysfunction by reversing cardiac fibrosis. In Aim 4 we will determine whether endogenous Ac-SDKP antagonizes the inflammatory and fibrotic effect of angiotensin II (Ang II), aldosterone, and myocardial infarction (MI). In addition, we will study whether part of the cardiovascular protective effect of ACEi is due to an increase in Ac-SDKP, which interacts with kinins and NO to decrease extracellular matrix deposition in the cardiovascular system. These studies are significant since they will demonstrate: 1) the mechanism by which Ac-SDKP decreases cardiac fibrosis; 2) whether it has a therapeutic effect, improving diastolic and systolic dysfunction by reversing cardiac fibrosis; 3) whether it has a physiological role by antagonizing pro-fibrotic stimuli in the cardiovascular system; and 4) whether it mediates the cardiovascular protective effect of ACEi. In the future, non-peptidic analogues of Ac-SDKP could be developed to treat fibrosis in hypertension, aging, heart failure (HF) post-MI, diabetes and other diseases.

描述：（申请人提供） 高血压是心血管危险因素，通常导致靶向器官 损害。血管紧张素转换酶抑制剂（ACEI）显着降低 心血管事件，特别是在高危患者中。 ACEI的影响 通过抑制ANG I向Ang II和Kinin的抑制来介导 降解。我们有证据表明在高血压中，另一种水解的另一种肽 通过ACE，N-乙酰基 - 甲基 - 乙酰基酰基 - 磷酸 - 丙烯酸酯（AC-SDKP），可防止和逆转 心脏纤维化而不改变血压（BP）或心脏细胞 肥大。这是AC-SDKP给药的第一次演示 对心脏纤维化有影响；但是，我们不知道AC-SDKP是否有 生理作用，抑制纤维化的机制，或者是 它有助于ACEI的心血管保护作用。在这个 我们建议测试高血压心脏的一般假设 纤维化是促纤维化之间平衡改变的结果 以及促炎性与抗纤维化和抗炎系统。 AC-SDKP 改变这种平衡，以支持后者，逆转纤维化（重要的 目标器官损伤的组成部分）和改善心脏功能。这 AC-SDKP拮抗促纤维化刺激的机制是：a）直接 通过抑制成纤维细胞增殖和胶原蛋白合成和b） 通过充当抗炎细胞因子间接地抑制 产生TGFβ1和其他细胞因子以及巨噬细胞激活以及 浸润。我们还假设 AC-SDKP协同相互作用介导目标器官损伤的ACEI介导 与Kinins和No。为了检验这一假设，我们建议在体内进行 研究，结合了生理，药理和分子 方法（基因删除）。在前两个目标中，我们将确定 AC-SDKP可防止并逆转心脏纤维化的机制。在目标1中 我们将研究其对成纤维细胞增殖和胶原蛋白合成的影响 和退化。在AIM 2中，我们将研究AC-SDKP是否抑制心脏 纤维化部分通过充当抗炎细胞因子，降低促炎性 细胞因子和巨噬细胞激活和浸润和反应性 氧生产。在AIM 3中，我们将研究是否在高血压方面 SDKP通过逆转心脏纤维化来改善舒张功能障碍。在目标4中我们 将确定内源性AC-SDKP是否拮抗炎症和 血管紧张素II（ANG II），醛固酮和心肌的纤维化作用 梗塞（MI）。此外，我们将研究是否部分 ACEI的心血管保护作用是由于AC-SDKP的增加， 它与基因蛋白相互作用，而不会减少细胞外基质沉积 在心血管系统中。这些研究很重要，因为它们会 证明：1）AC-SDKP降低心脏纤维化的机制； 2） 是否具有治疗作用，改善舒张压和收缩期 通过逆转心脏纤维化功能障碍； 3）它是否具有生理 通过在心血管系统中对促纤维化刺激作用来作用；和4） 它是否介导ACEI的心血管保护作用。在 未来，可以开发出AC-SDKP的非肽类似物来治疗纤维化 在高血压，衰老，心力衰竭（HF）MI后，糖尿病和其他 疾病。