Share This Article:

Polymyxin B Alleviates Angiotensin II-Induced Stress Fiber Formation and Cellular Hypertrophy

Abstract Full-Text HTML Download Download as PDF (Size:4682KB) PP. 903-910
DOI: 10.4236/pp.2014.59101    3,535 Downloads   4,016 Views  


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.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Oh, K. , Lee, J. , Oh, B. , Mun, J. , Park, B. and Lee, B. (2014) Polymyxin B Alleviates Angiotensin II-Induced Stress Fiber Formation and Cellular Hypertrophy. Pharmacology & Pharmacy, 5, 903-910. doi: 10.4236/pp.2014.59101.


[1] Chaponnier, C. and Gabbiani, G. (2004) Pathological Situations Characterized by Altered Actin Isoform Expression. Journal of Pathology, 204, 386-395.
[2] Olivetti, G., Melissari, M., Capasso, J.M. and Anversa, P. (1991) Cardiomyopathy of the Aging Human Heart. Myocyte Loss and Reactive Cellular Hypertrophy. Circulation Research, 68, 1560-1568.
[3] Zeidan, A., Javadov, S. and Karmazyn, M. (2006) Essential Role of Rho/ROCK-Dependent Processes and Actin Dynamics in Mediating Leptin-Induced Hypertrophy in Rat Neonatal Ventricular Myocytes. Cardiovascular Research, 72, 101-111.
[4] Balasubramanian, S., Mani, S.K., Kasiganesan, H., Baicu, C.C. and Kuppuswamy, D. (2010) Hypertrophic Stimulation Increases Beta-Actin Dynamics in Adult Feline Cardiomyocytes. PLoS ONE, 5, e11470.
[5] Oh, K.S., Oh, B.K., Park, C.H., Seo, H.W., Kang, N.S., Lee, J.H., Lee, J.S. and Lee, B.H. (2013) Cardiovascular Effects of a Novel Selective Rho Kinase Inhibitor, 2-(1H-Indazole-5-yl)Amino-4-Methoxy-6-Piperazino Triazine (DW1865). European Journal of Pharmacology, 702, 218-226.
[6] Moey, M., Rajapurohitam, V., Zeidan, A. and Karmazyn, M. (2011) Ginseng (Panax quinquefolius) Attenuates Leptin-Induced Cardiac Hypertrophy through Inhibition of p115Rho Guanine Nucleotide Exchange Factor-RhoA/Rho-Associated, Coiled-Coil Containing Protein Kinase-Dependent Mitogen-Activated Protein Kinase Pathway Activation. Journal of Pharmacology and Experimental Therapeutics, 339, 746-756.
[7] Evans, M.E., Feola, D.J. and Rapp, R.P. (1999) Polymyxin B Sulfate and Colistin: Old Antibiotics for Emerging Multiresistant Gram-Negative Bacteria. Annals of Pharmacotherapy, 33, 960-967.
[8] Zavascki, A.P., Goldani, L.Z., Li, J. and Nation, R.L. (2007) Polymyxin B for the Treatment of Multidrug-Resistant Pathogens: A Critical Review. Journal of Antimicrobial Chemotherapy, 60, 1206-1215.
[9] Murakami, M., Miyauchi, Y., Nishida, M., Okada, H. and Hamano, K. (2009) Direct Hemoperfusion Using Polymyxin-B Immobilized Fiber for Septic Shock after Cardiac Surgery. Circulation Journal, 73, 658-661.
[10] Sato, K., Maekawa, H., Sakurada, M., Orita, H. and Komatsu, Y. (2011) Direct Hemoperfusion with Polymyxin B Immobilized Fiber for Abdominal Sepsis in Europe. Surgery Today, 41, 754-760.
[11] Azad, M.A., Finnin, B.A., Poudyal, A., Davis, K., Li, J., Hill, P.A., Nation, R.L., Velkov, T. and Li, J. (2013) Polymyxin B Induces Apoptosis in Kidney Proximal Tubular Cells. Antimicrobial Agents and Chemotherapy, 57, 4329-4335.
[12] Harding, E.A., Jaggar, J.H., Squires, P.E. and Dunne, M.J. (1994) Polymyxin B Has Multiple Blocking Actions on the ATP-Sensitive Potassium Channel in Insulin-Secreting Cells. Pflugers Archiv: European Journal of Physiology, 426, 31-39.
[13] Ktenas, T.B., Sotiroudis, T.G. and Evangelopoulos, A.E. (1989) Effects of Polymyxin B on the Sarcoplasmic Reticulum Membrane. Bioscience Reports, 9, 573-578.
[14] Aida, Y., Pabst, M.J., Rademacher, J.M., Hatakeyama, T. and Aono, M. (1990) Effects of Polymyxin B on Superoxide Anion Release and Priming in Human Polymorphonuclear Leukocytes. Journal of Leukocyte Biology, 47, 283-291.
[15] Stutchfield, J., Jones, P.M. and Howell, S.L. (1986) The Effects of Polymyxin B, a Protein Kinase C Inhibitor, on Insulin Secretion from Intact and Permeabilized Islets of Langerhans. Biochemical and Biophysical Research Communications, 136, 1001-1006.
[16] Xu, F., Dai, C.L., Peng, S.L., Zhao, Y., Jia, C.J., Xu, Y.Q. and Zhao, C. (2014) Polymyxin B Protects against Hepatic Ischemia/Reperfusion Injury in a Rat Model of Obstructive Jaundice. Inflammation, 37, 1015-1021.
[17] Gysembergh, A., Margonari, H., Loufoua, J., Ovize, A., André-Fouët, X., Minaire, Y. and Ovize, M. (1998) Stretch-Induced Protection Shares a Common Mechanism with Ischemic Preconditioning in Rabbit Heart. American Journal of Physiology-Heart and Circulatory Physiology, 274, H955-H964.
[18] Yelich, M.R., Schieber, C.K., Umporowicz, D.M. and Filkins, J.P. (1992) Polymyxin-B Suppresses Endotoxin-Induced Insulin Hypersecretion in Pancreatic Islets. Circulatory Shock, 38, 85-90.
[19] McKinsey, T.A. and Kass, D.A. (2007) Small-Molecule Therapies for Cardiac Hypertrophy: Moving beneath the Cell Surface. Nature Reviews Drug Discovery, 6, 617-635.
[20] Sin, Y.Y. and Baillie, G.S. (2012) Protein Kinase D in the Hypertrophy Pathway. Biochemical Society Transactions, 40, 287-289.
[21] Belmonte, S.L. and Blaxall, B.C. (2012) G Protein-Coupled Receptor Kinase 5: Exploring Its Hype in Cardiac Hypertrophy. Circulation Research, 111, 957-958.
[22] Ishizaka, N., Alexander, R.W., Laursen, J.B., Kai, H., Fukui, T., Oppermann, M., Lefkowitz, R.J., Lyons, P.R. and Griendling, K.K. (1997) G Protein-Coupled Receptor Kinase 5 in Cultured Vascular Smooth Muscle Cells and Rat Aorta. Regulation by Angiotensin II and Hypertension. Journal of Biological Chemistry, 272, 32482-32488.
[23] Thiyagarajan, M.M., Stracquatanio, R.P., Pronin, A.N., Evanko, D.S., Benovic, J.L. and Wedegaertner, P.B. (2004) A Predicted Amphipathic Helix Mediates Plasma Membrane Localization of GRK5. Journal of Biological Chemistry, 279, 17989-17995.
[24] Martini, J.S., Raake, P., Vinge, L.E., DeGeorge Jr., B.R., Chuprun, J.K., Harris, D.M., Gao, E., Eckhart, A.D., Pitcher, J.A. and Koch, W.J.(2008) Uncovering G Protein-Coupled Receptor Kinase-5 as a Histone Deacetylase Kinase in the Nucleus of Cardiomyocytes. Proceedings of the National Academy of Sciences of the United States of America, 105, 12457-12462.

comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.