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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn356
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Coupling factor 6 enhances Src-mediated responsiveness to angiotensin II in resistance arterioles and cells

Tomohiro Osanai, M.D., Hirofumi Tomita, M.D., Motoi Kushibiki, M.D., Masahiro Yamada, M.D., Makoto Tanaka, PhD., Toshihiro Ashitate, M.D., Takashi Echizen, M.D., Chisato Katoh, M.D., Koji Magota, Ph.D.* and Ken Okumura, M.D.

Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Correspondence to: Tomohiro Osanai, M.D. Department of Cardiology Hirosaki University Graduate School of Medicine 5 Zaifu-Cho, Hirosaki, 036-8562 Japan Tel: 81-172-39-5057 Fax: 81-172-35-9190 e-mail: osanait{at}cc.hirosaki-u.ac.jp

Aim: Coupling factor 6 (CF6) induces hypertension by attenuating the endothelial generation of prostacyclin. However, intracellular signaling of CF6 in the resistance arteriole vascular smooth muscle cells (VSMC) that is directly related to vasoconstriction has not been determined. Here we investigated the direct effect of exogenous CF6 on Ca2+ signaling in cultured VSMC and the in vivo role of endogenous CF6 in the genesis of hypertension using CF6 transgenic (TG) mice.

Methods and Results: CF6 induced a monophasic increase in the intracellular free Ca2+ concentration ([Ca2+]i) through nifedipine-sensitive Ca2+ channels in A7r5 cells, a cell line of VSMC, and enhanced the angiotensin II-induced spike phase of [Ca2+]i to a greater degree in VSMC derived from spontaneously hypertensive rats (SHR). In the mesenteric arterioles obtained from CF6-TG mice that manifested hypertension, angiotensin II-induced vasoconstriction was enhanced compared with wild-type mice, and its enhancement was abolished by anti-CF6 antibody. Pretreatment with PP1, a tyrosine kinase c-Src inhibitor, blocked CF6-induced increase in Ca2+ signaling in VSMC and vasoconstriction in TG mice. The receptor of CF6 was F1 motor of ATP synthase with a higher affinity in SHR. CF6 decreased intracellular pH via activation of ATPase activity and led to c-Src activation to a greater degree in SHR-derived VSMC.

Conclusion: CF6 causes hypertension by directly enhancing Ca2+ signaling in VSMC and vasoconstriction in the mesenteric arteriolar network via c-Src activation.

Time for primary review: 40 Days

* Asubio Pharma Co., Ltd., Biomedical Center, Biopharma Research Department, Biotechnology Group, 2716-1, Kurakake, Akaiwa, Chiyoda-machi, Ohra-gun, Gunma-ken, 370-0503, Japan


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