Hypertension and Collagen: Effect of Ac-SDKP

高血压和胶原蛋白：Ac-SDKP 的作用

• 批准号: 6558190
• 负责人: NOUR-EDDINE RHALEB
• 金额: $ 28.6万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6558190
• 关键词: ACE inhibitors; antiinflammatory agents; cell proliferation; collagen; cytoprotection; drug design /synthesis /production; drug screening /evaluation; enzyme induction /repression; enzyme substrate; fibroblasts; fibrosis; growth inhibitors; heart cell; hypertension; laboratory rat; mitogen activated protein kinase; oligopeptides; peptidyl dipeptidase A; protein kinase C; transforming growth factors; ventricular hypertrophy

DESCRIPTION (provided by applicant): Hypertension causes left ventricular hypertrophy (LVH) and increased LV interstitial and perivascular collagen deposition. Increased cardiac collagen may alter function in hypertrophied hearts. Angiotensin converting enzyme inhibition(ACEi) has been shown to reverse LVH in hypertension. This effect has been attributed to blockade of angiotensin II (Ang II) formation and kinin degradation. We have shown that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), another natural substrate for ACE, prevents LV monocyte/macrophage infiltration and fibrosis without altering blood pressure (BP) or LVH in hypertension. We believe this is the first demonstration that Ac-SDKP affects cardiac fibrosis; however, the mechanism(s) or receptor(s) by which Ac-SDKP affords cardioprotection are not known, nor whether Ac-SDKP contributes to the cardioprotective effects of ACEi. We hypothesize that (1) Ac-SDKP has an anti-inflammatory and antifibrotic effect on the heart in hypertension via specific receptor(s) linked to a cascade of signal transduction, including MAP kinase, protein kinase C (PKC), NF-kB and TGF-beta, and (2) the effect of ACEi on the heart is mediated in part by Ac-SDKP. In aim new analogues of Ac-SDKP and SDK fragments will be synthesized and tested to identify (1) an ACE-resistant analogue with an inhibitory effect similar to Ac-SDKP that can be radiolabeled and used to characterize Ac-SDKP receptor(s), and (2) an antagonist that specifically blocks the inhibitory effect of Ac-SDKP. In aim II we will determine whether (1) the effect of Ac- SDKP is linked to suppression of TGF-beta, CTGF and Smad expression, and (2) the effect of TGF-beta on collagen type I and/or III expression is affected by Ac-SDKP. We will also examine whether Ac-SDKP inhibits p38 and PKC activation in fibroblasts. In aim IV we will determine whether in vivo Ac-SDKP (1) inhibits inflammatory cell infiltration in the LV, p42/p44, p38 and/or PKC activity, NF-kB,TGF-beta, CTGF and Smads, (2) regresses cardiac fibroblast proliferation, collagen expression and synthesis, (3) increases matrix metalloproteinase activity, and (4) decreases cardiac expression of collagen I and III in rats with long-term hypertension. In aim IV we will examine whether the effect of ACE inhibitionon LV collagen deposition is mediated by Ac-SDKP. This project will provide important new information on the on the cardioprotective effect of ACEi in hypertension and the mechanism of action of Ac-SDKP.

描述（由申请人提供）：高血压导致左心室肥厚（LVH）并增加左心室间质和血管周围胶原沉积。 心脏胶原蛋白的增加可能会改变肥大心脏的功能。 血管紧张素转换酶抑制 (ACEi) 已被证明可以逆转高血压引起的 LVH。 这种效应归因于血管紧张素 II (Ang II) 形成和激肽降解的阻断。 我们已经证明，ACE 的另一种天然底物 N-乙酰基-丝氨酰-天冬氨酰-赖氨酰-脯氨酸 (Ac-SDKP) 可以防止左心室单核细胞/巨噬细胞浸润和纤维化，而不改变高血压 (BP) 或 LVH。 我们相信这是 Ac-SDKP 影响心脏纤维化的首次证明；然而，Ac-SDKP 提供心脏保护作用的机制或受体以及 Ac-SDKP 是否有助于 ACEi 的心脏保护作用尚不清楚。 我们假设 (1) Ac-SDKP 通过与信号转导级联相关的特定受体（包括 MAP 激酶、蛋白激酶 C (PKC)、NF-kB 和 TGF-β）对高血压患者的心脏具有抗炎和抗纤维化作用；(2) ACEi 对心脏的作用部分由 Ac-SDKP 介导。 我们将合成并测试 Ac-SDKP 和 SDK 片段的新类似物，以鉴定 (1) 具有与 Ac-SDKP 类似抑制作用的 ACE 抗性类似物，可进行放射性标记并用于表征 Ac-SDKP 受体，以及 (2) 特异性阻断 Ac-SDKP 抑制作用的拮抗剂。 在目标 II 中，我们将确定 (1) Ac-SDKP 的作用是否与抑制 TGF-β、CTGF 和 Smad 表达有关，以及 (2) TGF-β 对 I 型和/或 III 型胶原蛋白表达的作用是否受 Ac-SDKP 影响。 我们还将检查 Ac-SDKP 是否抑制成纤维细胞中 p38 和 PKC 的激活。 在目标 IV 中，我们将确定体内 Ac-SDKP 是否 (1) 抑制 LV、p42/p44、p38 和/或 PKC 活性、NF-kB、TGF-β、CTGF 和 Smads 中的炎症细胞浸润，(2) 抑制心脏成纤维细胞增殖、胶原蛋白表达和合成，(3) 增加基质金属蛋白酶 (4) 降低长期高血压大鼠心脏 I 型和 III 型胶原蛋白的表达。 在目标 IV 中，我们将检查 ACE 抑制对 LV 胶原沉积的影响是否是由 Ac-SDKP 介导的。 该项目将为 ACEi 对高血压的心脏保护作用以及 Ac-SDKP 的作用机制提供重要的新信息。