Arginine vasopressin stimulates proliferation of adult rat cardiac fibroblasts via protein kinase C-extracellular signal-regulated kinase 1/2 pathway

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HE Yan-Ping(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
ZHAO Lian-You(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
ZHENG Qiang-Sun(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
LIU Shao-Wei(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
ZHAO Xiao-Yan(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
LU Xiao-Long(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
NIU Xiao-Lin(Department of Cardiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China)
Journal Title:
Volume 60, Issue 03, 2008
Key Word:
arginine vasopressin;V1 receptor;extracellular sigual-regulated kinase 1/2;protein kinase C;p27Klp1;cyclin;cardiac fibroblast

Abstract: Arginine vasopressin (AVP), a neurohormone and hemodynamic factor implicated in the pathophysiology of hypertension and congestive heart failure, can also act as a growth-stimulating factor. Our previous work demonstrated that AVP is a mitogen for neonatal rat cardiac fibroblasts (CFs). In the present study, we extended our investigations to adult rat CFs to explore whether AVP could induce adult rat CF proliferation and, if so, to identify the mechanism involved. Adult rat CFs were isolated, cultured and subjected to AVP treatment. DNA synthesis and cell cycle distribution were analyzed by [3H]-thymidine incorporation and flow cytometry. Cellular extracellular signal-regulated kinase 1/2 (ERK 1/2) activity was measured by in vitro kinase assay using myelin basic protein (MBP) as a substrate. Protein expressions of total-and phospho-ERK1/2, p27Kip1, cyclins D1, A, E were assessed by Western blot. The results showed that AVP stimulated DNA synthesis in adult rat CFs, and the effect was abolished by a V1 receptor antagonist, d(CH2)5[Tyr2(Me),Arg8-vasopressin (0.1μmol/L), but not by a V2 receptor antagonist, desglycinamide-[d(CH2)5, D-Ile2, Ile4, Arg8-vasopressin (0.1μmol/L). AVP induced an activation of ERK1/2, which could be mimicked by the protein kinase C (PKC) activator, phorbol 12-myfistate 13-acetate (PMA, 30nmol/L, 5min), but abolished by depiction of PKC via chronic PMA incubation (2.5μmol/L,24h). In addition, AVP down-regulated protein expression of p27Kip1, increased protein expressions of cyclins D1, A and E, and induced cell cycle progression from G0/G1 into S stage. Inhibition of ERK1/2 activation by PD98059 (30μmol/L) abolished the effect of AVP on DNA synthesis, protein expressions of p27Klp1, cyclins D1, A and E as well as cell cycle progression. These results suggest that AVP is also a growth factor for adult rat CFs. The mitogenic effect of AVP is mediated via V1 receptors and PKC-ERK 1/2 pathway. Moreover, AVP modulates the expressions of cell cycle regulatory proteins p27Kip1 and cyclins D1, A and E, which lie downstream of ERK 1/2 activation, and induces cell cycle progression in adult rat CFs.

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