TITLE:
Polymyxin B Alleviates Angiotensin II-Induced Stress Fiber Formation and Cellular Hypertrophy
AUTHORS:
Kwang-Seok Oh, Jeong Hyun Lee, Byung Koo Oh, Jihye Mun, Byung Kil Park, Byung Ho Lee
KEYWORDS:
Polymyxin B, GRK5, Angiotensin II, Actin Stress Fiber, Cellular Hypertrophy
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.5 No.9,
August
21,
2014
ABSTRACT:
Polymyxin B is
widely used antibiotic in the clinic for resistant Gram-negative infections. In
addition, polymyxin B-immobilized hemoperfusion cartridge has been used for
endotoxin removal therapy in patients with septic shock. The aim of this study
was to investigate the anti-fibrotic and anti-cellular hypertrophic effects of
polymyxin B, and further to explore its possible mechanism. Polymyxin B (3, 10
μM) significantly inhibited stress fiber formation induced by angiotensin II
(Ang II) in rat heart-derived H9c2 cells. Furthermore, polymyxin B (1 - 10 μM)
showed a potent inhibitory effect on Ang II-induced cellular hypertrophy in
H9c2 cells. Under the mechanism study, the inhibitory activities of polymyxin B
against kinases involved in cellular hypertrophy such as AKT1, CAMK, GRK5, GSK3β, MLCK, PKC, PKD2, AMPK, ROCK2, p70S6K,
SGK1were evaluated. Polymyxin B possesses a potent G protein related kinase 5
(GKR5) inhibitory activity with IC50 value of 1.1 μM, and has an ATP
non-competitive inhibitory mode. Taken together, these results indicate that
polymyxin B alleviates Ang II-induced stress fiber formation and cellular
hypertrophy, and propose that one mechanism underlying these effects involves
inhibition of the GRK5 pathway.