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Involvement of Histamine 2 Receptor in Alpha 1 Adrenoceptor Mediated Cardiac Hypertrophy and Oxidative Stress in H9c2 Cardio Myoblasts

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Abstract

Despite the involvement of ɑ1adrenergic (ɑ1AR) and Histamine 2 receptors (H2R) in cardiac hypertrophy (CH), their relationship is yet to be studied. Our study investigated interrelationship between them using in vitro CH model. H9c2 cardiomyoblasts were exposed to phenylephrine (ɑ1AR agonist-50 μM) in the presence, the absence of famotidine (H2R antagonist-10 μM) and BAY 11-7082 (NF-kB inhibitor-10 μM). The impact of ɑ1AR stimulation on H2R expression and oxidative stress was assessed. Hypertrophic indices were assessed from activities of enzymatic mediators of cardiac hypertrophy, total protein content, BNP levels and cell volume. Additionally, the inverse agonistic property of famotidine and NFkB activity was also studied. ɑ1AR-induced H2R expression, oxidative stress and hypertrophic indices were significantly abolished by famotidine and pharmacological inhibitor of NFkB. Increase in constitutive activity of H2R was noticed correlating with increased receptor population. These results suggest involvement of NFkB-mediated upregulation of H2R in ɑ1AR-mediated CH.

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Abbreviations

AR:

Adrenergic receptors

BST:

Bryostatin 1

BUR:

Burimamide

Fam:

Famotidine

H2R:

Histamine 2 receptor

PE:

Phenylephrine

References

  1. Triposkiadis, F., Karayannis, G., Giamouzis, G., Skoularigis, J., Louridas, G., & Butler, J. (2009). The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. Journal of the American College of Cardiology, 54(19), 1747–1762. https://doi.org/10.1016/j.jacc.2009.05.015.

    Article  CAS  PubMed  Google Scholar 

  2. Porter, K. E., & Turner, N. A. (2009). Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacology & Therapeutics, 123(2), 255–278. https://doi.org/10.1016/j.pharmthera.2009.05.002.

    Article  CAS  Google Scholar 

  3. Lim, H. W., Windt, L. J. D., Steinberg, L., Taigen, T., Witt, S. A., Kimball, T. R., & Molkentin, J. D. (2000). Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy. Circulation, 101(20), 2431–2437. https://doi.org/10.1161/01.CIR.101.20.2431.

    Article  CAS  PubMed  Google Scholar 

  4. Cooling, M., Hunter, P., & Crampin, E. J. (2007). Modeling hypertrophic IP3 transients in the cardiac Myocyte. Biophysical Journal, 93(10), 3421–3433. https://doi.org/10.1529/biophysj.107.110031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sakata, Y., Hoit, B. D., Liggett, S. B., Walsh, R. A., & Dorn, G. W. (1998). Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation, 97(15), 1488–1495.

    Article  CAS  Google Scholar 

  6. Pönicke, K., Vogelsang, M., Heinroth, M., Becker, K., Zolk, O., Böhm, M., et al. (1998). Endothelin receptors in the failing and nonfailing human heart. Circulation, 97(8), 744–751.

    Article  Google Scholar 

  7. Clark, W. A., Rudnick, S. J., Andersen, L. C., & LaPres, J. J. (1994). Myosin heavy chain synthesis is independently regulated in hypertrophy and atrophy of isolated adult cardiac myocytes. The Journal of Biological Chemistry, 269(41), 25562–25569.

    Article  CAS  Google Scholar 

  8. Clark, W. A., Rudnick, S. J., LaPres, J. J., Andersen, L. C., & LaPointe, M. C. (1993). Regulation of hypertrophy and atrophy in cultured adult heart cells. Circulation Research, 73(6), 1163–1176.

    Article  CAS  Google Scholar 

  9. Ikeda, U., Tsuruya, Y., & Yaginuma, T. (1991). Alpha 1-adrenergic stimulation is coupled to cardiac myocyte hypertrophy. The American Journal of Physiology, 260(3 Pt 2), H953–H956.

    CAS  PubMed  Google Scholar 

  10. Fuller, S. J., Gaitanaki, C. J., & Sugden, P. H. (1990). Effects of catecholamines on protein synthesis in cardiac myocytes and perfused hearts isolated from adult rats. Stimulation of translation is mediated through the alpha 1-adrenoceptor. The Biochemical Journal, 266(3), 727–736.

    Article  CAS  Google Scholar 

  11. Knowlton, K. U., Baracchini, E., Ross, R. S., Harris, A. N., Henderson, S. A., Evans, S. M., et al. (1991). Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression. The Journal of Biological Chemistry, 266(12), 7759–7768.

    Article  CAS  Google Scholar 

  12. Bishopric, N. H., Simpson, P. C., & Ordahl, C. P. (1987). Induction of the skeletal alpha-actin gene in alpha 1-adrenoceptor-mediated hypertrophy of rat cardiac myocytes. The Journal of Clinical Investigation, 80(4), 1194–1199. https://doi.org/10.1172/JCI113179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kariya, K., Farrance, I. K., & Simpson, P. C. (1993). Transcriptional enhancer factor-1 in cardiac myocytes interacts with an alpha 1-adrenergic- and beta-protein kinase C-inducible element in the rat beta-myosin heavy chain promoter. The Journal of Biological Chemistry, 268(35), 26658–26662.

    Article  CAS  Google Scholar 

  14. Long, C. S., Ordahl, C. P., & Simpson, P. C. (1989). Alpha 1-adrenergic receptor stimulation of sarcomeric actin isogene transcription in hypertrophy of cultured rat heart muscle cells. The Journal of Clinical Investigation, 83(3), 1078–1082. https://doi.org/10.1172/JCI113951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Seddon, M., Looi, Y. H., & Shah, A. M. (2007). Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart, 93(8), 903–907. https://doi.org/10.1136/hrt.2005.068270.

    Article  CAS  PubMed  Google Scholar 

  16. Gaitanaki, C., Konstantina, S., Chrysa, S., & Beis, I. (2003). Oxidative stress stimulates multiple MAPK signalling pathways and phosphorylation of the small HSP27 in the perfused amphibian heart. The Journal of Experimental Biology, 206(Pt 16), 2759–2769.

    Article  CAS  Google Scholar 

  17. Heineke, J., & Molkentin, J. D. (2006). Regulation of cardiac hypertrophy by intracellular signalling pathways. Nature reviews. Molecular and Cellular Biology, 7(8), 589–600. https://doi.org/10.1038/nrm1983.

    Article  CAS  Google Scholar 

  18. He, H., Liu, X., Lv, L., Liang, H., Leng, B., Zhao, D., et al. (2014). Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress. Cell Death & Disease, 5, e997. https://doi.org/10.1038/cddis.2013.533.

    Article  CAS  Google Scholar 

  19. Takimoto, E., & Kass, D. A. (2007). Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension, 49(2), 241–248. https://doi.org/10.1161/01.HYP.0000254415.31362.a7.

    Article  CAS  PubMed  Google Scholar 

  20. Xu, Q., Dalic, A., Fang, L., Kiriazis, H., Ritchie, R., Sim, K., et al. (2011). Myocardial oxidative stress contributes to transgenic β2-adrenoceptor activation-induced cardiomyopathy and heart failure. British Journal of Pharmacology, 162(5), 1012–1028. https://doi.org/10.1111/j.1476-5381.2010.01043.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Di Lisa, F., Kaludercic, N., & Paolocci, N. (2011). β2–Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another “radical” road to heart failure? British Journal of Pharmacology, 162(5), 1009–1011. https://doi.org/10.1111/j.1476-5381.2010.01130.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Haenen, G. R., Veerman, M., & Bast, A. (1990). Reduction of beta-adrenoceptor function by oxidative stress in the heart. Free Radical Biology & Medicine, 9(4), 279–288.

    Article  CAS  Google Scholar 

  23. Hara, M., Ono, K., Hwang, M.-W., Iwasaki, A., Okada, M., Nakatani, K., et al. (2002). Evidence for a role of mast cells in the evolution to congestive heart failure. The Journal of Experimental Medicine, 195(3), 375–381.

    Article  CAS  Google Scholar 

  24. Dvorak, A. M. (1986). Mast-cell degranulation in human hearts. The New England Journal of Medicine, 315(15), 969–970.

    CAS  PubMed  Google Scholar 

  25. Luo, T., Chen, B., Zhao, Z., He, N., Zeng, Z., Wu, B., et al. (2013). Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function. Basic Research in Cardiology, 108(3), 342. https://doi.org/10.1007/s00395-013-0342-4.

    Article  CAS  PubMed  Google Scholar 

  26. Zeng, Z., Shen, L., Li, X., Luo, T., Wei, X., Zhang, J., et al. (2014). Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis. Clinical Science (London, England : 1979), 127(7), 435–448. https://doi.org/10.1042/CS20130716.

    Article  CAS  Google Scholar 

  27. Potnuri, A. G., Allakonda, L., Appavoo, A., Saheera, S., & Nair, R. R. (2016). Targeting histamine-2 receptor for prevention of cardiac remodelling in chronic pressure overload. International Journal of Cardiology, 202, 831–833. https://doi.org/10.1016/j.ijcard.2015.10.040.

    Article  PubMed  Google Scholar 

  28. Takahama, H., Asanuma, H., Sanada, S., Fujita, M., Sasaki, H., Wakeno, M., et al. (2010). A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade. Basic Research in Cardiology, 105(6), 787–794. https://doi.org/10.1007/s00395-010-0119-y.

    Article  CAS  PubMed  Google Scholar 

  29. Ahmadi, A., Ebrahimzadeh, M. A., Ahmad-Ashrafi, S., Karami, M., Mahdavi, M. R., & Saravi, S. S. S. (2011). Hepatoprotective, antinociceptive and antioxidant activities of cimetidine, ranitidine and famotidine as histamine H2 receptor antagonists. Fundamental & Clinical Pharmacology, 25(1), 72–79. https://doi.org/10.1111/j.1472-8206.2009.00810.x.

    Article  CAS  Google Scholar 

  30. Kesiova, M., Alexandrova, A., Yordanova, N., Kirkova, M., & Todorov, S. (2006). Effects of diphenhydramine and famotidine on lipid peroxidation and activities of antioxidant enzymes in different rat tissues. Pharmacological reports: PR, 58(2), 221–228.

    CAS  PubMed  Google Scholar 

  31. Herman, F. F., Goldberg, B. J., Lad, P. M., Neidzin, H., Kaplan, M., & Easton, J. G. (1990). Effects of histamine on alpha adrenergic receptor expression on the lymphocytes of normal and asthmatic subjects. Annals of Allergy, 65(1), 32–36.

    CAS  PubMed  Google Scholar 

  32. Rius, R. A., Mollner, S., Pfeuffer, T., & Peng Loh, Y. (1994). Developmental changes in Gs and golf proteins and adenylyl cyclases in mouse brain membranes. Brain Research, 643(1–2), 50–58. https://doi.org/10.1016/0006-8993(94)90007-8.

    Article  CAS  PubMed  Google Scholar 

  33. Fraga, C. G., Leibovitz, B. E., & Tappel, A. L. (1988). Lipid peroxidation measured as thiobarbituric acid-reactive substances in tissue slices: characterization and comparison with homogenates and microsomes. Free Radical Biology and Medicine, 4(3), 155–161. https://doi.org/10.1016/0891-5849(88)90023-8.

    Article  CAS  PubMed  Google Scholar 

  34. Weydert, C. J., & Cullen, J. J. (2010). Measurement of superoxide dismutase, catalase, and glutathione peroxidase in cultured cells and tissue. Nature Protocols, 5(1), 51–66. https://doi.org/10.1038/nprot.2009.197.

    Article  CAS  PubMed  Google Scholar 

  35. Li, R., Jen, N., Yu, F., & Hsiai, T. K. (2011). Assessing mitochondrial redox status by flow cytometric methods: vascular response to fluid shear stress. Current protocols in cytometry/editorial board, J. Paul Robinson, managing editor ... [et al.], CHAPTER, Unit9.37. doi:https://doi.org/10.1002/0471142956.cy0937s58.

  36. Eruslanov, E., & Kusmartsev, S. (2010). Identification of ROS using oxidized DCFDA and flow-cytometry. Methods in Molecular Biology (Clifton, N.J.), 594, 57–72. https://doi.org/10.1007/978-1-60761-411-1_4.

    Article  CAS  Google Scholar 

  37. Knowles, J. W., Esposito, G., Mao, L., Hagaman, J. R., Fox, J. E., Smithies, O., et al. (2001). Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice. Journal of Clinical Investigation, 107(8), 975–984.

    Article  CAS  Google Scholar 

  38. Nadruz, W. (2015). Myocardial remodeling in hypertension. Journal of Human Hypertension, 29(1), 1–6. https://doi.org/10.1038/jhh.2014.36.

    Article  CAS  PubMed  Google Scholar 

  39. Aceros, H., Farah, G., Cobos-Puc, L., Stabile, A., Noiseux, N., & Mukaddam-Daher, S. (2011). Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt. British Journal of Pharmacology, 164(3), 946–957. https://doi.org/10.1111/j.1476-5381.2011.01355.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Potnuri, A. G., Allakonda, L., Appavoo, A., Saheera, S., & Nair, R. R. (2018). Association of histamine with hypertension-induced cardiac remodeling and reduction of hypertrophy with the histamine-2-receptor antagonist famotidine compared with the beta-blocker metoprolol. Hypertension Research: Official Journal of the Japanese Society of Hypertension, 41(12), 1023–1035. https://doi.org/10.1038/s41440-018-0109-2.

    Article  CAS  Google Scholar 

  41. Kim, J., Ogai, A., Nakatani, S., Hashimura, K., Kanzaki, H., Komamura, K., et al. (2006). Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. Journal of the American College of Cardiology, 48(7), 1378–1384. https://doi.org/10.1016/j.jacc.2006.05.069.

    Article  CAS  PubMed  Google Scholar 

  42. Khilnani, G., & Khilnani, A. K. (2011). Inverse agonism and its therapeutic significance. Indian Journal of Pharmacology, 43(5), 492–501. https://doi.org/10.4103/0253-7613.84947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Monczor, F. (2006). Mechanisms of inverse agonism at histamine H(2) receptors - potential benefits and concerns. Inflammopharmacology, 14(1–2), 89–96. https://doi.org/10.1007/s10787-006-1516-6.

    Article  CAS  PubMed  Google Scholar 

  44. Baker, J. G., Hall, I. P., & Hill, S. J. (2003). Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. Molecular Pharmacology, 64(6), 1357–1369. https://doi.org/10.1124/mol.64.6.1357.

    Article  CAS  PubMed  Google Scholar 

  45. Lai, L., Yan, L., Gao, S., Hu, C.-L., Ge, H., Davidow, A., et al. (2013). Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of MnSOD via the SIRT1/FoxO3a pathway. Circulation, CIRCULATIONAHA, 113, 001212. https://doi.org/10.1161/CIRCULATIONAHA.112.001212.

    Article  CAS  Google Scholar 

  46. Matsushima, S., Ide, T., Yamato, M., Matsusaka, H., Hattori, F., Ikeuchi, M., et al. (2006). Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation, 113(14), 1779–1786. https://doi.org/10.1161/CIRCULATIONAHA.105.582239.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge and show gratitude for the support extended by the National Institute of Pharmaceutical Education and Research, Hyderabad for permitting us to utilize their research facilities.

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Correspondence to Ajay Godwin Potnuri.

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ESM 1

Raw Western Blot images. (a-b) the pictorial representation of PRX3 and corresponding Beta actin (c-d)) the pictorial representation of H2R and corresponding Beta actin (PNG 1790 kb)

High Resolution (TIF 1653 kb)

ESM 2

Melt curve images. (a) the pictorial representation of melt curves for fig. 7c (b)) the pictorial representation of melt curves for fig. 7d (JPG 220 kb)

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Potnuri, A.G., Allakonda, L. & Saheera, S. Involvement of Histamine 2 Receptor in Alpha 1 Adrenoceptor Mediated Cardiac Hypertrophy and Oxidative Stress in H9c2 Cardio Myoblasts. J. of Cardiovasc. Trans. Res. 14, 184–194 (2021). https://doi.org/10.1007/s12265-020-09967-6

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