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 I V 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 I V 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===========================================
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