Effect of N-acetyl-seryl-aspartyl-lysyl-proline on DNA and collagen synthesis in rat cardiac fibroblasts

被引:99
作者
Rhaleb, NE [1 ]
Peng, HM [1 ]
Harding, P [1 ]
Tayeh, M [1 ]
LaPointe, MC [1 ]
Carretero, OA [1 ]
机构
[1] Henry Ford Hosp, Hypertens & Vasc Res Div, Detroit, MI 48202 USA
关键词
amino acid; angiotensin-converting enzyme inhibitors fibroblasts; collagen; endothelin; protein kinases;
D O I
10.1161/01.HYP.37.3.827
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell entry into the S phase of the cell cycle and is normally present in human plasma. Ac-SDKP is exclusively hydrolyzed by ACE, and its plasma concentration is increased 5-fold after ACE inhibition in humans. We examined the effect of 0.05 to 100 nmol/L Ac-SDKP on 24-hour-H-3-thymidine incorporation (DNA synthesis) by cardiac fibroblasts both in the absence and presence of 5% FCS. Captopril (1 mu mol/L) was added in all cases to prevent the degradation of Ac-SDKP. Treatment of cardiac fibroblasts with 5% FCS increased thymidine incorporation from a control value of 12 469+/-594 to 24 598+/-1051 cpm (P<0.001). Cotreatment with 1 nmol/L Ac-SDKP reduced stimulation to control levels (10 373+/-200 cpm, P<0.001), We measured hydroxyproline content and incorporation of H-3-proline into collagenous fibroblast proteins and found that Ac-SDKP blocked endothelin-1 (10(-8) mol/L)-induced collagen synthesis in a biphasic and dose-dependent manner, causing inhibition at low doses, whereas high doses had little or no effect. It also blunted the activity of p44/p42 mitogen-activated protein kinase in a biphasic and dose-dependent manner in serum-stimulated fibroblasts, suggesting that the inhibitory effect of DNA and collagen synthesis may depend in part on blocking mitogen-activated protein kinase activity. Participation of p44/p42 in collagen synthesis was confirmed, because a specific inhibitor for p44/p42 activation (PD 980591 25 mu mol/L) was able to block endothelin-I-induced collagen synthesis, similar to the effect of Ac-SDKP, The fact that Ac-SDKP inhibits DNA and collagen synthesis in cardiac fibroblasts suggests that it may be an important endogenous regulator of fibroblast proliferation and collagen synthesis in the heart. Ac-SDKP may participate in the cardioprotective effect of ACE inhibitors by limiting fibroblast proliferation (and hence collagen production), and therefore it would reduce fibrosis in patients with hypertension.
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收藏
页码:827 / 832
页数:6
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