Colchicine, a Microtubule Depolymerizing Agent, Inhibits Myocardial Apoptosis in Rats

Colchicine, a Microtubule Depolymerizing Agent, Inhibits Myocardial Apoptosis in Rats

KENYA SAJI,¹ YOSHIHIRO FUKUMOTO,¹ JUN SUZUKI,¹ SHIGEFUMI FUKUI,¹ JUN NAWATA¹ and HIROAKI SHIMOKAWA^1,2

¹Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
²The Technology Agency, CREST, Tokyo, Japan

Heart failure is the most common cardiovascular disease with high mortality and morbidity. Both enhanced microtubule polymerization and cardiomyocyte apoptosis are involved in the pathogenesis of heart failure. However, the link between the two mechanisms remains to be elucidated. In this study, we thus address this important issue in cultured cardiomyocytes from Wistar rats in vitro and in angiotensin II (ATII)-infused rats in vivo. Confocal microscopy examination showed that in cultured rat cardiomyocytes, micrographic density of microtubules was increased by paclitaxel, a microtubule-polymerizing agent, and decreased by colchicine, a microtubule-depolymerizing agent, but not affected by ATII, isoproterenol, or tumor necrosis factor-α alone. Immunoblotting analysis showed that Bax/Bcl-2 ratio, which is associated with the activation of caspase-3, was significantly increased in ATII-stimulated cultured cardiomyocytes in vitro and in ATII-infused rats in vivo, both of which were inhibited by co-treatment with colchicine. Caspase-3 and TUNEL assay to detect apoptosis in vitro demonstrated that paclitaxel or ATII alone significantly enhanced and their combination further accelerated cardiomyocyte apoptosis, which was again significantly inhibited by colchicine. Caspase-3 and TUNEL assay in vivo also demonstrated that ATII infusion significantly increased myocardial apoptosis and that co-treatment with colchicine significantly suppressed the apoptosis. In conclusion, these results indicate that a microtubule-depolymerizing agent could be a potential therapeutic strategy for treatment of heart failure.

keywords —— apoptosis; myocytes; microtubule; polymerization; colchicine

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Tohoku J. Exp. Med., 2007, 213, 139-148

Correspondence: Yoshihiro Fukumoto, M.D., Ph.D., Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

e-mail: fukumoto@cardio.med.tohoku.ac.jp