Colchicine, a microtubule depolymerizing agent, inhibits myocardial apoptosis in rats.
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-alpha 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.
Saji
Kenya
K
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Fukumoto
Yoshihiro
Y
Suzuki
Jun
J
Fukui
Shigefumi
S
Nawata
Jun
J
Shimokawa
Hiroaki
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D020287:In Situ Nick-End Labeling; D008297:Male; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; D050257:Tubulin Modulators; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D003078:Colchicine