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 I V 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 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL071806-01
Application #
6558190
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
2003-01-01
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$286,000
Indirect Cost
Name
Henry Ford Health System
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Worou, Morel E; Liao, Tang-Dong; D'Ambrosio, Martin et al. (2015) Renal protective effect of N-acetyl-seryl-aspartyl-lysyl-proline in dahl salt-sensitive rats. Hypertension 66:816-22
González, Germán E; Rhaleb, Nour-Eddine; Nakagawa, Pablo et al. (2014) N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats. Clin Sci (Lond) 126:85-94
Xu, Jiang; Carretero, Oscar A; Zhu, Liping et al. (2013) Protective role of AT(2) and B(1) receptors in kinin B(2)-receptor-knockout mice with myocardial infarction. Clin Sci (Lond) 124:87-96
Rhaleb, Nour-Eddine; Pokharel, Saraswati; Sharma, Umesh C et al. (2013) N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1*-mediated matrix metalloproteinase activation in cardiac fibroblasts. Pflugers Arch 465:1487-95
Nakagawa, Pablo; Liu, Yunhe; Liao, Tang-Dong et al. (2012) Treatment with N-acetyl-seryl-aspartyl-lysyl-proline prevents experimental autoimmune myocarditis in rats. Am J Physiol Heart Circ Physiol 303:H1114-27
Peng, Hongmei; Carretero, Oscar A; Peterson, Edward L et al. (2012) N-Acetyl-seryl-aspartyl-lysyl-proline inhibits ET-1-induced collagen production by preserving Src homology 2-containing protein tyrosine phosphatase-2 activity in cardiac fibroblasts. Pflugers Arch 464:415-23
Zhu, Liping; Carretero, Oscar A; Xu, Jiang et al. (2012) Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1. Am J Physiol Heart Circ Physiol 302:H2553-9
Rhaleb, Nour-Eddine; Pokharel, Saraswati; Sharma, Umesh et al. (2011) Renal protective effects of N-acetyl-Ser-Asp-Lys-Pro in deoxycorticosterone acetate-salt hypertensive mice. J Hypertens 29:330-8
Rhaleb, Nour-Eddine; Yang, Xiao-Ping; Carretero, Oscar A (2011) The kallikrein-kinin system as a regulator of cardiovascular and renal function. Compr Physiol 1:971-93
Peng, Hongmei; Yang, Xiao-Ping; Carretero, Oscar A et al. (2011) Angiotensin II-induced dilated cardiomyopathy in Balb/c but not C57BL/6J mice. Exp Physiol 96:756-64

Showing the most recent 10 out of 24 publications