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大（LVH）和LV间质和血管周围胶原沉积增加。 心脏胶原蛋白的增加可能改变肥大心脏的功能。 血管紧张素转换酶抑制剂（ACEi）已被证明可以逆转高血压患者的LVH。 这种作用归因于血管紧张素II（Ang II）形成和激肽降解的阻断。 我们已经表明，N-乙酰-丝氨酰-乙酰-赖氨酰-脯氨酸（Ac-SDKP），ACE的另一种天然底物，可防止LV单核细胞/巨噬细胞浸润和纤维化，而不改变高血压（BP）或LVH。 我们认为这是Ac-SDKP影响心脏纤维化的首次证明;然而，Ac-SDKP提供心脏保护的机制或受体尚不清楚，Ac-SDKP是否有助于ACEi的心脏保护作用。 我们假设（1）Ac-SDKP通过与信号传导级联相关的特异性受体（包括MAP激酶、蛋白激酶C（PKC）、NF-kB和TGF-β）对高血压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。 目的是合成Ac-SDKP和SDK片段的新类似物并进行检测，以鉴定（1）具有与Ac-SDKP相似的抑制作用的ACE耐药类似物，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。 在目的II中，我们将确定（1）Ac-SDKP的作用是否与TGF-β、CTGF和Smad表达的抑制有关，和（2）TGF-β对I型和/或III型胶原表达的作用是否受Ac-SDKP影响。 我们还将检查Ac-SDKP是否抑制成纤维细胞中的p38和PKC活化。 在目的IV中，我们将确定体内Ac-SDKP是否（1）抑制LV中的炎性细胞浸润、p42/p44、p38和/或PKC活性、NF-κ B、TGF-β、CTGF和Smads，（2）使心脏成纤维细胞增殖、胶原表达和合成消退，（3）增加基质金属蛋白酶活性，（4）降低长期高血压大鼠心肌I、III型胶原的表达。 在目的IV中，我们将研究ACE抑制对LV胶原沉积的影响是否是由Ac-SDKP介导的。 本项目将为ACEi在高血压中的心脏保护作用和Ac-SDKP的作用机制提供重要的新信息。