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P21 (Cdc42/Rac)-activated kinase 1 (pak1) is associated with cardiotoxicity induced by antihistamines

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Abstract

Astemizole, a non-sedating histamine H1 receptor blocker, is widely known to cause cardiac arrhythmia, which prolongs the QT interval. However, the precise molecular mechanism involved in antihistamine-induced cardiovascular adverse effects other than hERG channel inhibition is still unclear. In this study, we used DNA microarray analysis to detect the mechanisms involved in life-threatening adverse effects caused by astemizole. Rat primary cardiomyocytes were treated with various concentrations of astemizole for 24 h and the corresponding cell lysates were analyzed using a DNA microarray. Astemizole altered the expression profiles of genes involved in calcium transport/signaling. Using qRT-PCR analysis, we demonstrated that, among those genes, p21 (Cdc42/Rac)-activated kinase 1 (pak1) mRNA was downregulated by treatment with terfenadine and astemizole. Astemizole also reduced pak1 protein levels in rat cardiomyocytes. In addition, astemizole decreased pak1 mRNA and protein levels in H9c2 cells and induced an increase in cell surface area (hypertrophy) and cytotoxicity. Fingolimod hydrochloride (FTY720), a pak1 activator, inhibited astemizole-induced hypertrophy and cytotoxicity in H9c2 cells. These results suggest that antihistamine-induced cardiac adverse effects are associated with pak1 expression and function.

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References

  • Aplin AE, Juliano RL (1999) Integrin and cytoskeletal regulation of growth factor signaling to the MAP kinase pathway. J Cell Sci 112(5):695–706

    CAS  PubMed  Google Scholar 

  • Ashoor R, Yafawi R, Jessen B, Lu S (2013) The contribution of lysosomotropism to autophagy perturbation. PloS One 8:e82481

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbey JT, Anderson M, Ciprandi G, Frew AJ, Morad M, Priori SG, Ongini E, Affrime MB (1999) Cardiovascular safety of second-generation antihistamines. Am J Rhinol 13:235–243

    Article  CAS  PubMed  Google Scholar 

  • Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803

    Article  CAS  PubMed  Google Scholar 

  • Davis MJ, Wu X, Nurkiewicz TR, Kawasaki J, Gui P, Hill MA, Wilson E (2002) Regulation of ion channels by integrins. Cell Biochem Biophys 36:41–66

    Article  CAS  PubMed  Google Scholar 

  • De Ponti F, Poluzzi E, Montanaro N (2000) QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 56:1–18

    Article  PubMed  Google Scholar 

  • Delgado LF, Pferferman A, Sole D, Naspitz CK (1998) Evaluation of the potential cardiotoxicity of the antihistamines terfenadine, astemizole, loratadine, and cetirizine in atopic children. Ann Allerg Asthma Immunol 80:333–337

    Article  CAS  Google Scholar 

  • Dubuske LM (1999) Second-generation antihistamines: the risk of ventricular arrhythmias. Clin Ther 21:281–295

    Article  CAS  PubMed  Google Scholar 

  • Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109:1580–1589

    Article  PubMed  Google Scholar 

  • Gralinski MR (2000) The assessment of potential for QT interval prolongation with new pharmaceuticals: impact on drug development. J Pharmacol Toxicol Methods 43:91–99

    Article  CAS  PubMed  Google Scholar 

  • Howarth PH, Emanuel MB, Holgate ST (1984) Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels. Br J Clin Pharmacol 18:1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda S, Oka H, Matunaga K, Kubo S, Asai S, Miyahara Y, Osaka A, Kohno S (1998) Astemizole-induced torsades de pointes in a patient with vasospastic angina. Jpn Circ J 62:225–227

    Article  CAS  PubMed  Google Scholar 

  • Jeong K, Kwon H, Min C, Pak Y (2009) Modulation of the caveolin-3 localization to caveolae and STAT3 to mitochondria by catecholamine-induced cardiac hypertrophy in H9c2 cardiomyoblasts. Exp Mol Med 41:226–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke Y, Lei M, Solaro RJ (2008) Regulation of cardiac excitation and contraction by p21 activated kinase-1. Prog Biophys Mol Biol 98:238–250

    Article  CAS  PubMed  Google Scholar 

  • Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH (1991) Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 114:345–352

    Article  CAS  PubMed  Google Scholar 

  • Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, Murabito JM, Vasan RS (2002) Long-term trends in the incidence of and survival with heart failure. N Engl J Med 347:1397–1402

    Article  PubMed  Google Scholar 

  • Liu W, Zi M, Naumann R, Ulm S, Jin J, Taglieri DM, Prehar S, Gui J, Tsui H, Xiao RP, Neyses L, Solaro RJ, Ke Y, Cartwright EJ, Lei M, Wang X (2011) Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart. Circulation 124:2702–2715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olasinska-Wisniewska A, Olasinski J, Grajek S (2014) Cardiovascular safety of antihistamines. Postepy Dermatol Alergol 31:182–186

    Article  PubMed  PubMed Central  Google Scholar 

  • Paakkari I (2002) Cardiotoxicity of new antihistamines and cisapride. Toxicol Lett 127:279–284

    Article  CAS  PubMed  Google Scholar 

  • Park MJ, Lee KR, Shin DS, Chun HS, Kim CH, Ahn SH, Bae MA (2013) Predicted drug-induced bradycardia related cardio toxicity using a zebrafish in vivo model is highly correlated with results from in vitro tests. Toxicol Lett 216:9–15

    Article  CAS  PubMed  Google Scholar 

  • Pietrzkowicz M, Grzelewska-Rzymowska I (1999) Second generation topical antihistaminics. Pol Merkur Lek 6:277–280

    CAS  Google Scholar 

  • Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    Article  CAS  PubMed  Google Scholar 

  • Sheehan KA, Ke Y, Solaro RJ (2007) p21-Activated kinase-1 and its role in integrated regulation of cardiac contractility. Am J Physiol Regul Integr Comp Physiol 293:R963–R973

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama A, Aye NN, Katahira S, Saitoh M, Hagihara A, Matsubara Y, Hashimoto K (1997) Effects of nonsedating antihistamine, astemizole, on the in situ canine heart assessed by cardiohemodynamic and monophasic action potential monitoring. Toxicol Appl Pharmacol 143:89–95

    Article  CAS  PubMed  Google Scholar 

  • Taglialatela M, Pannaccione A, Castaldo P, Giorgio G, Zhou Z, January CT, Genovese A, Marone G, Annunziato L (1998) Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines. Mol Pharmacol 54:113–121

    CAS  PubMed  Google Scholar 

  • Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Genovese A, Marone G, Annunziato L (1999) Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity. Clin Exp Allergy 29(Suppl 3):182–189

    Article  CAS  PubMed  Google Scholar 

  • Tsui H, Zi M, Wang S, Chowdhury SK, Prehar S, Liang Q, Cartwright EJ, Lei M, Liu W, Wang X (2015) Smad3 couples pak1 with the antihypertrophic pathway through the E3 ubiquitin ligase, Fbxo32. Hypertension 66:1176–1183

    CAS  PubMed  Google Scholar 

  • Van Der Wees CG, Bax WH, Van Der Valk EJ, Van Der Laarse A (2006) Integrin stimulation induces calcium signaling in rat cardiomyocytes by a NO-dependent mechanism. Pflugers Arch 451:588–595

    Article  CAS  PubMed  Google Scholar 

  • Welch MJ, Meltzer EO, Simons FE (2002) H1-antihistamines and the central nervous system. Clin Allergy Immunol 17:337–388

    CAS  PubMed  Google Scholar 

  • Wu X, Sun Z, Foskett A, Trzeciakowski JP, Meininger GA, Muthuchamy M (2010) Cardiomyocyte contractile status is associated with differences in fibronectin and integrin interactions. Am J Physiol Heart Circ Physiol 298:H2071–H2081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto K, Tamura T, Imai R, Yamamoto M (2001) Acute canine model for drug-induced Torsades de Pointes in drug safety evaluation-influences of anesthesia and validation with quinidine and astemizole. Toxicol Sci 60:165–176

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Wu X, Gui P, Wu J, Sheng JZ, Ling S, Braun AP, Davis GE, Davis MJ (2010) Alpha5beta1 integrin engagement increases large conductance, Ca2+-activated K+ channel current and Ca2+ sensitivity through c-src-mediated channel phosphorylation. J Biol Chem 285:131–141

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by a grant (15181MFDS482, 08171MFDS503, 07151MFDS671) from the Ministry of Food and Drug Safety.

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    Authors and Affiliations

    1. Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea

      Jaesuk Yun, So Young Kim, Kyung Sik Yoon, Heejung Shin, Ho-Sang Jeong, Hyejoo Chung, Young-Hoon Kim, Jisoon Shin, Hye Jin Cha, Kyoung moon Han, Seungha Hyeon, Tac-hyung Lee, Hye-Kyung Park & Hyung Soo Kim

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    1. Jaesuk Yun
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    Jaesuk Yun and So Young Kim contributed equally to this work.

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    Yun, J., Kim, S.Y., Yoon, K.S. et al. P21 (Cdc42/Rac)-activated kinase 1 (pak1) is associated with cardiotoxicity induced by antihistamines. Arch. Pharm. Res. 39, 1644–1652 (2016). https://doi.org/10.1007/s12272-016-0840-7

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