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

He Yanping, Zhao Lianyou, Sun Qiangsun, Liu Shaowei, Zhao Xiaoyan, Lu Xiaolong, Niu Xiaolin

Department of Cardiology,Tangdu Hospital,the Fourth Military Medical University.Xi'an 710038,Shaanxi

Abstract

Arginine vasopressin (AVP), a neurohormone and hemodynamic factor, is 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 [~(3)H]-thymidine incorporation and flow cytometry. Cellular extracellular signal-regulated kinase 1/2 (ERK1/2) activity was measured by in vitro kinase assay using myelin basic protein (MBP) as a substrate. Protein expressions of total- and phospho- ERK1/2, p27~(Kip1), cyclin D1, A, E were assessed by Western blot. Results showed that AVP stimulated DNA synthesis in adult rat CFs, an effect abolished by the V1 receptor antagonist, d(CH_(2))_(5)[Tyr~(2)(Me), Arg~(8)]-vasopressin (0.1 #mu#mol/L), but not by the V2 receptor antagonist, desglycinamide-[d(CH_(2))_(5), D-Ile~(2), Ile~(4), Arg~(8)]-vasopressin (0.1 #mu#mol/L). AVP induced an activation of ERK1/2, which could be mimicked by the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA, 30 nmol/L, 5 min), but abolished by depletion of PKC via chronic PMA incubation (2.5 #mu#mol/L, 24 h). In addition, AVP down-regulated protein expression of p27~(Kip1), increased expressions of cyclins D1, A and E, and induced cell cycle progression from G_(0)/G_(1) into S stage. Inhibition of ERK1/2 activation by PD98059 (30 #mu#mol/L) abolished the effect of AVP on DNA synthesis, protein expressions of p27~(Kip1), 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 the type 1 vasopressin receptor and PKC-ERK1/2 pathway. Moreover, AVP modulates the expressions of cell cycle regulatory proteins p27~(Kip1) and cyclins D1, A and E, which lie downstream of ERK1/2 activation, and induces cell cycle progression in adult rat CFs.

Key words: Arginine vasopressin;V1 receptor;Extracellular signal-regulated kinase 1/2;Protein kinase C;p27~(Kip1);cyclin;Cardiac fibroblast

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Citing This Article：

He Yanping, Zhao Lianyou, Sun Qiangsun, Liu Shaowei, Zhao Xiaoyan, Lu Xiaolong, Niu Xiaolin. Arginine vasopressin stimulates proliferation of adult rat cardiac fibroblasts via protein kinase C--extracellular signal--regulated kinase 1/2 pathway. Acta Physiol Sin 2008; 60 (3): 333-340 (in Chinese with English abstract).