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.
Highlights
Physiological and pathological adaptations of cell are responses to stress that allow cells to modulate their structure and lead to escape injury
Effects of Polymyxin B on Cellular Hypertrophy In H9c2 cells treated with Ang Angiotensin II Dulbecco’s modified Eagle’s medium (DMEM) (II) (0.3 μM) alone (Control (+)) for 4 consecutive days, cell size was significantly increased by approximately 1.51 ± 0.17 times (Figure 2)
The angiotensin II (Ang II)-induced cellular hypertrophy was significantly inhibited by pretreatment with polymyxin B (p < 0.05 at 1 - 10 μM) in a concentration-dependent manner. 3.3
Summary
Physiological and pathological adaptations of cell are responses to stress that allow cells to modulate their structure and lead to escape injury. Stress fiber formation as well as cellular hypertrophy belongs to the adaptive cell response to various stimuli. Inappropriate regulation of stress fiber formation and hypertrophic cell growth is directly involved in numerous pathological situations, including cardiovascular disease and cancer [1] [2]. The suppression of stress fiber formation and cellular hypertrophy are considered a promising pharmacological strategy for cardiovascular diseases, and a number of inhibitors have been developed [5] [6]. Polymyxin B is a cyclic polypeptide antibiotic produced by the soil bacterium Paenibacillus polymixa [7]. It has re-emerged in clinical practice due to increasing prevalence and incidence of nosocomial infections caused by multidrug-resistance Gram-negative infections [8]. In the present study, we investigate the anti-fibrotic as well as anti-hypertrophic effects of polymyxin B in H9c2 cells and further explore the possible mechanism underlying these effects of polymyxin B
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