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) 高血压是心血管疾病的危险因素，通常会导致靶器官 损坏。血管紧张素转换酶抑制剂显著降低 心血管事件，特别是在高危患者中。血管紧张素转换酶抑制剂的作用 通过抑制血管紧张素转换为血管紧张素转换和激动素 退化。我们有证据表明高血压患者体内的另一种多肽 通过ACE，N-乙酰-丝氨酸-天冬氨酰-赖氨酸(Ac-SDKP)，预防和逆转 不改变血压(BP)或心肌细胞的心脏纤维化 肥大。这是第一次展示ac-sdkp的管理。 对心肌纤维化有影响；然而，我们不知道ac-sdKP是否有 生理作用，抑制纤维化的机制，还是 这与ACEI的心血管保护作用有关。在这 我们提出的项目是检验一般假设，即在高血压心脏 纤维化是前肝纤维化平衡改变的结果。 以及促炎VS抗纤维化和抗炎系统。AC-SDKP 改变这种平衡，有利于后者，逆转纤维化(一个重要的 靶器官损害的组成部分)和改善心脏功能。这个 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合成，以及b) 通过作为抗炎细胞因子间接发挥作用，从而抑制 转化生长因子β1等细胞因子的产生和巨噬细胞的激活 渗透。我们还假设其抗肝纤维化作用的一部分 ACEI在靶器官损伤中的作用与Ac-SDKP的协同作用 用金宁和不用。为了验证这一假设，我们建议在体内进行 研究，使用生理学、药理学和分子的组合 方法(基因缺失)。在前两个目标中，我们将确定 Ac-sdKP预防和逆转心肌纤维化的机制。在目标1中 我们将研究其对成纤维细胞增殖和胶原合成的影响。 和退化。在目标2中，我们将研究Ac-SDKP是否抑制心脏 纤维化部分通过作为抗炎细胞因子发挥作用，减少促炎作用 细胞因子与巨噬细胞活化、渗透和反应 氧气的产生。在目标3中，我们将研究高血压患者是否存在高血压。 SDKP通过逆转心肌纤维化改善舒张期功能障碍。在Aim 4中，我们 将确定内源性Ac-SDKP是否拮抗炎性和 血管紧张素II(Ang II)、醛固酮和心肌纤维化的作用 心肌梗死(MI)。此外，我们会研究是否会有部分 ACEI的心血管保护作用是通过增加Ac-SDKP， 它与激动素和一氧化氮相互作用，减少细胞外基质沉积 在心血管系统中。这些研究具有重要意义，因为它们将 论证：1)Ac-SDKP减轻心肌纤维化的机制；2) 是否有疗效，改善舒缩功能 逆转心肌纤维化所致的功能障碍；3)是否具有生理性 在心血管系统中通过拮抗促纤维化刺激的作用；以及4) 是否介导了ACEI的心血管保护作用。在 未来，ac-SDKP的非肽类似物可被开发用于治疗纤维化。 高血压、衰老、心肌梗死后心力衰竭、糖尿病和其他 疾病。