Mitogenic effect of arginine vasopressin on adult rat cardiac fibroblast: involvement of PKC-erk1/2 pathway.
Arginine vasopressin (AVP) has been implicated in the pathophysiology of cardiac hypertrophy. We previously demonstrated that AVP is a mitogen for neonatal rat cardiac fibroblasts (CFs). In the present study, we extend our investigation to adult rat CFs to explore whether AVP could induce adult rat CFs proliferation and, if so, to identify the underlying mechanisms. We found that AVP stimulated cell proliferation, an effect abolished by V1 receptor antagonist, d(CH2)5[Tyr2(Me), Arg8]-vasopressin, but not V2 receptor antagonist, desglycinamide-[d(CH2)5, D-Ile2, Ile4, Arg8]-vasopressin. AVP also activated extracellular signal-regulated kinase 1/2 (erk1/2), a response mimicked by protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), but abolished by depleting cellular PKC through chronic PMA incubation. Calphostin C, an inhibitor of PKC, attenuated and PMA mimicked the effect of AVP on cell proliferation, whereas Ca2+ chelating agent 1,2-bis(2-aminophenoxy)ethane N, N, N', N'-tetraacetic acid (BAPTA) had no effect. Further, AVP downregulated protein expression of p27Kip1, increased cyclins D1, A, and E expressions and induced cell cycle progression through G0/G1 into S stage. Antisense oligonucleotides against cyclins D1, A, and E decreased cell number in the presence of AVP. Whereas antisense treatment against p27Kip1 and overexpression of p27Kip1 exerted a stimulatory and inhibitory effect, respectively. Inhibiting erk1/2 activation by PD98059 abolished the effect of AVP on cell proliferation, cell cycle regulatory proteins, and cell cycle progression. These results suggest that AVP is a mitogen for adult rat CFs via the mediation of V1 receptor and PKC-erk1/2 pathway.
Yan-ping
He
H
Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
Lian-you
Zhao
Z
Qiang-sun
Zheng
Z
Shao-wei
Liu
L
Xiao-yan
Zhao
Z
Xiao-long
Lu
L
Xiao-lin
Niu
N
Xia
Li
L
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000494:pharmacology / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D008938:Mitosis; D009206:Myocardium / Q000166:cytology*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism
D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3