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Involvement of ERK and AKT signaling in the growth effect of arginine vasopressin on adult rat cardiac fibroblast and the modulation by simvastatin

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Abstract

Arginine vasopressin (AVP) has been shown to directly induce neonatal rat cardiac fibroblasts (CFs) proliferation, a major component involved in cardiac hypertrophy. Herein, we explored whether AVP is also a growth factor for adult rat CFs and, if so, whether the growth effect could be inhibited by simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. AVP significantly increased DNA synthesis in adult rat CFs by 73.5 ± 5.1% (P ≤ 0.05), an effect inhibited by V1 receptor antagonist, d(CH2)5[Tyr2(Me), Arg8]-vasopressin. AVP also activated extracellular signal-regulated kinase 1/2 (ERK1/2) as assessed by MBP phosphotransferase activity (5.1 ± 0.6 fold over basal level, P ≤ 0.05) and Western blot analysis, and effects were mimicked by protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), but abolished by inhibiting cellular PKC through chronic PMA incubation. In addition, AVP induced PKC activation (27.2 ± 3.8% from a basal value of 9.3 ± 0.7%, P ≤ 0.05). AVP-induced increase in DNA synthesis could be attenuated by the specific inhibitors of ERK1/2 (PD98059), PI3K (LY294002), and AKT (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, HIMO). Simvastatin inhibited the effects of AVP on DNA synthesis, ERK1/2, and PKC activation in a dose-dependent manner. Phosphatidylinositol-3-kinase (PI3K)-dependent AKT activation induced by AVP was also inhibited by simvastatin. The effects of simvastatin on ERK1/2, PKC, and AKT activation and DNA synthesis could be reversed by mevalonate. These results support a growth-inducing effect of AVP on adult rat CFs through ERK and AKT signalings and the growth effect could be attenuated by simvastatin via inhibiting these two pathways.

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Acknowledgments

We thank Shang Fu-jun, Liu Hui and Zhang Li-juan for their valuable and kind technical assistance and helpful suggestions. We also thank Zeng Chun-yu for his careful proofreading on grammatical English of the manuscript and constructive comments on our article.

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Authors and Affiliations

  1. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, No. 1, Xinsi Street, Baqiao District, Xi’an, Shaanxi, 710038, People’s Republic of China

    Yan-Ping He, Lian-You Zhao, Qiang-Sun Zheng, Shao-Wei Liu, Xiao-Yan Zhao, Xiao-Long Lu & Xiao-Lin Niu

  2. Institute of Aviation Medicine, Air Force PLA, Beijing, 100036, People’s Republic of China

    Xia Li

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  1. Yan-Ping He
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Correspondence to Lian-You Zhao.

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He, YP., Zhao, LY., Zheng, QS. et al. Involvement of ERK and AKT signaling in the growth effect of arginine vasopressin on adult rat cardiac fibroblast and the modulation by simvastatin. Mol Cell Biochem 317, 33–41 (2008). https://doi.org/10.1007/s11010-008-9802-9

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  • DOI: https://doi.org/10.1007/s11010-008-9802-9

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