Pflügers Archiv - European Journal of Physiology

, Volume 464, Issue 4, pp 415–423

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

  • Hongmei Peng
  • Oscar A. Carretero
  • Edward L. Peterson
  • Xiao-Ping Yang
  • Kastuv Santra
  • Nour-Eddine Rhaleb
Original Paper

DOI: 10.1007/s00424-012-1150-7

Cite this article as:
Peng, H., Carretero, O.A., Peterson, E.L. et al. Pflugers Arch - Eur J Physiol (2012) 464: 415. doi:10.1007/s00424-012-1150-7

Abstract

N–Acetyl–seryl–aspartyl–lysyl–proline (Ac-SDKP) inhibits endothelin-1 (ET-1)-induced activation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) and collagen production in cultured rat cardiac fibroblasts (RCFs). However, we do not know whether its inhibitory effect on p44/42 MAPK is due to the altered activity of protein tyrosine phosphatases (PTPs), which in turn downregulate the p44/42 MAPK signaling pathway. The activity of Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2) is downregulated by ET-1 in RCFs; thus, we hypothesized that Ac-SDKP inhibits ET-1-stimulated collagen production in part by preserving SHP-2 activity and thereby inhibiting p44/42 MAPK phosphorylation. When we stimulated RCFs with ET-1 in the presence or absence of Ac-SDKP, we found that (a) PTP activity was reduced by ET-1 and (b) this effect was counteracted by Ac-SDKP in a dose-dependent fashion. Next, we extracted SHP-2 from RCF lysates by immunoprecipitation and determined that (a) ET-1 inhibited SHP-2 by 40 % and (b) this effect was prevented by Ac-SDKP. However, Ac-SDKP failed to inhibit ET-1-induced p44/42 MAPK phosphorylation in RCFs treated with SHP-2 short hairpin RNA (shRNA); in contrast, in cells transfected with control shRNA, Ac-SDKP’s inhibitory effect on ET-1-induced p44/42 MAPK activation remained intact. Moreover, the inhibitory effect of Ac-SDKP on ET-1-stimulated collagen production was blunted in cells treated with the SHP-1/2 inhibitor NSC-87877. Thus, we concluded that the inhibitory effect of Ac-SDKP on ET-1-stimulated collagen production by RCFs is mediated in part by preserving SHP-2 activity and thereby preventing p44/42 MAPK activation. Ac-SDKP or its analogs could represent a new therapeutic tool to treat fibrotic diseases in the cardiovascular system.

Keywords

Endothelin-1 Cardiac fibroblasts Src homology 2-containing protein tyrosine phosphatase-2 Ac-SDKP Collagen 

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Hongmei Peng
    • 1
  • Oscar A. Carretero
    • 1
  • Edward L. Peterson
    • 3
  • Xiao-Ping Yang
    • 1
  • Kastuv Santra
    • 1
  • Nour-Eddine Rhaleb
    • 1
    • 2
  1. 1.Hypertension and Vascular Research Division, Department of Internal MedicineHenry Ford HospitalDetroitUSA
  2. 2.Department of PhysiologyWayne State UniversityDetroitUSA
  3. 3.Department of Biostatistics and Research EpidemiologyHenry Ford HospitalDetroitUSA

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