Hypertension and Collagen: Effect of Ac-SDKP

超出所提供的空间。高血压引起左室肥厚（LVH）和左室间质和血管周围胶原沉积增加。心肌胶原蛋白增加可能改变肥厚心脏的功能。血管紧张素转换酶抑制（ACEi）已被证明可以逆转高血压患者的LVH。这种作用归因于阻断血管紧张素II （Ang II）的形成和激肽的降解。我们已经证明，另一种ACE的天然底物n -乙酰基-seryl-天冬氨酸-赖氨酸-脯氨酸（Ac-SDKP）可以防止左室单核细胞/巨噬细胞浸润和纤维化，而不会改变高血压患者的血压（BP）或LVH。我们认为这是首次证明Ac-SDKP影响心脏纤维化；然而，Ac-SDKP提供心脏保护的机制或受体尚不清楚，也不知道Ac-SDKP是否有助于ACEi的心脏保护作用。我们假设(1)Ac-SDKP通过与一系列信号转导相关的特定受体，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。目的是合成和测试新的Ac-SDKP和SDK片段类似物，以鉴定(1)具有与Ac-SDKP相似的抑制作用的ace耐药类似物，可以放射性标记并用于表征Ac-SDKP受体(s)，以及(2)特异性阻断Ac-SDKP抑制作用的拮抗剂。在aim 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型胶原表达的作用是否受到Ac-SDKP的影响。我们还将研究Ac-SDKP是否抑制成纤维细胞中的sp38和PKC激活。在目的IV中，我们将确定体内Ac-SDKP是否(1)抑制左室炎症细胞浸润、p42/p44、p38和/或PKC活性、NF-kB、tgf - β、CTGF和Smads，(2)抑制心脏成纤维细胞增殖、胶原表达和合成，(3)增加基质金属蛋白酶活性，(4)降低长期高血压大鼠心脏I和III胶原表达。在目的IV中，我们将研究ACE抑制左室胶原沉积的作用是否由Ac-SDKP介导。本项目将为ACEi在高血压中的心脏保护作用和ACEi - sdkp的作用机制提供重要的新信息。PERFORMANCESITE ( ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Hypertension causes left ventricular hypertrophy (LVH) and increased LV interstitialand perivascular collagen deposition. Increased cardiac collagen may alter function in hypertrophied hearts. Angiotensin- converting enzyme inhibition(ACEi) haves 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 shownthat N-acetyl-seryl-aspartyl-lysyl-proline(Ac-SDKP), another natural substrate for ACE, prevents LV monocyte/macrophage infiltrationand fibrosiswithout 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 cardioprotectionare not known, nor whether Ac-SDKP contributes to the cardioprotectiveeffects of ACEi. We hypothesizethat (1) Ac-SDKP has an anti-inflammatoryand antifibroticeffect on the heart in hypertension via specific receptor(s) linkedto 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 blocksthe 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 inhibitsp38 and PKC activationin fibroblasts. In aim IV we will determine whether in vivo Ac-SDKP (1) inhibitsinflammatory cell infiltrationin 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. PERFORMANCESITE( ========================================Section End===========================================