PP  Vol.5 No.9 , August 2014
Polymyxin B Alleviates Angiotensin II-Induced Stress Fiber Formation and Cellular Hypertrophy
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.
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.