Molecular and Cellular Biochemistry

, Volume 366, Issue 1–2, pp 287–297 | Cite as

Role of NF-κB and p38 MAPK activation in mediating angiotensin II and endothelin-1-induced stimulation in leptin production and cardiomyocyte hypertrophy

  • Venkatesh Rajapurohitam
  • Ana Kilic
  • Sabzali Javadov
  • Morris Karmazyn


We recently identified leptin as a downstream factor mediating the hypertrophic effects of both angiotensin II and endothelin-1 in cardiomyocytes, an effect dependent on increased leptin biosynthesis, however, the mechanism for such increased leptin production is not known. This study was designed to elucidate the mechanisms underlying angiotensin II- and endothelin-1-stimulated synthesis in cultured ventricular myocytes. The hypertrophic effects of both angiotensin II (100 nM) and endothelin-1 (10 nM) were associated with increased leptin secretion and gene expression by 40 and 50 %, and 86 and 68 %, respectively. These effects were associated with significantly increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation by 34 and 52 %, as well as enhanced translocation of NF-κB into nuclei and also the NF-κB-DNA binding activity by 35 and 31 % induced by angiotensin II and endothelin-1, respectively. On their own, 24 h treatment with either angiotensin II or endothelin-1 increased cell surface area by 30 and 40 %, protein synthesis by 30 % and the α-skeletal actin gene by 53 and 68 %, respectively, indicating a robust hypertrophic effect whereas this was completely prevented by NF-κB inhibition. In addition, NF-κB inhibition significantly attenuated angiotensin II and endothelin-1-induced p38 MAPK activation whereas inhibition of p38 MAPK blocked both angiotensin II- and endothelin-1-induced increases in leptin secretion. The ability of both angiotensin II- and endothelin-1 to increase leptin production in cardiomyocytes and the resultant hypertrophic response are mediated by NF-κB and dependent on p38 MAPK activation.


Leptin NF-κB Angiotensin II Endothelin-1 MAPK Cardiomyocyte hypertrophy 



This study was supported by a grant (MOP62764) from the Canadian Institutes of Health Research. AK held a Postdoctoral Research Award from the Heart and Stroke Foundation of Canada during the course of these studies. MK is a Canada Research Chair in Experimental Cardiology.


  1. 1.
    Toth MJ, Gottlieb SS, Fisher ML, Ryan AS, Nicklas BJ, Poehlman ET (1997) Plasma leptin concentrations and energy expenditure in heart failure patients. Metabolism 46:450–453PubMedCrossRefGoogle Scholar
  2. 2.
    Leyva F, Anker SD, Egerer K, Stevenson JC, Kox WJ, Coats AJ (1998) Hyperleptinaemia in chronic heart failure. Relationships with insulin. Eur Heart J 19:1547–1551PubMedCrossRefGoogle Scholar
  3. 3.
    Moro C, Grauzam S, Ormezzano O, Toufektsian MC, Tanguy S, Calabrese P, Coll JL, Bak I, Juhasz B, Tosaki A, de Leiris J, Boucher F (2011) Inhibition of cardiac leptin expression after infarction reduces subsequent dysfunction. J Cell Mol Med 15:1688–1694PubMedCrossRefGoogle Scholar
  4. 4.
    McGaffin KR, Moravec CS, McTiernan CF (2009) Leptin signaling in the failing and mechanically unloaded human heart. Circ Heart Fail 2:676–683PubMedCrossRefGoogle Scholar
  5. 5.
    Purdham DM, Rajapurohitam V, Zeidan A, Huang C, Gross GJ, Karmazyn M (2008) A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart. Am J Physiol Heart Circ Physiol 295:H441–H446PubMedCrossRefGoogle Scholar
  6. 6.
    Pedersen EB, Danielsen H, Jensen T, Madsen M, Sorensen SS, Thomsen OO (1986) Angiotensin II, aldosterone and arginine vasopressin in plasma in congestive heart failure. Eur J Clin Invest 16:56–60PubMedCrossRefGoogle Scholar
  7. 7.
    Kinugawa T, Kato M, Ogino K, Osaki S, Igawa O, Hisatome I, Shigemasa C (2003) Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure. J Card Fail 9:318–324PubMedCrossRefGoogle Scholar
  8. 8.
    Rajapurohitam V, Javadov S, Purdham DM, Kirshenbaum LA, Karmazyn M (2006) An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. J Mol Cell Cardiol 41:265–274PubMedCrossRefGoogle Scholar
  9. 9.
    Purcell NH, Tang G, Yu C, Mercurio F, DiDonato JA, Lin A (2001) Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. Proc Natl Acad Sci USA 98:6668–6673PubMedCrossRefGoogle Scholar
  10. 10.
    Hirotani S, Otsu K, Nishida K, Higuchi Y, Morita T, Nakayama H, Yamaguchi O, Mano T, Matsumura Y, Ueno H, Tada M, Hori M (2002) Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy. Circulation 105:509–515PubMedCrossRefGoogle Scholar
  11. 11.
    Doi T, Sakoda T, Akagami T, Naka T, Mori Y, Tsujino T, Masuyama T, Ohyanagi M (2008) Aldosterone induces interleukin-18 through endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in cardiomyocytes. Am J Physiol Heart Circ Physiol 295:H1279–H1287PubMedCrossRefGoogle Scholar
  12. 12.
    Sarman B, Skoumal R, Leskinen H, Rysa J, Ilves M, Soini Y, Tuukkanen J, Pikkarainen S, Lako-Futo Z, Papp L, deChatel R, Toth M, Ruskoaho H, Szokodi I (2007) Nuclear factor-kappaB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling. J Hypertens 25:1927–1939PubMedCrossRefGoogle Scholar
  13. 13.
    Gupta S, Young D, Maitra RK, Gupta A, Popovic ZB, Yong SL, Mahajan A, Wang Q, Sen S (2008) Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol 375:637–649PubMedCrossRefGoogle Scholar
  14. 14.
    Li H, Shi S, Sun YH, Zhao YJ, Li QF, Li HZ, Wang R, Xu CQ (2009) Dopamine D2 receptor stimulation inhibits angiotensin II-induced hypertrophy in cultured neonatal rat ventricular myocytes. Clin Exp Pharmacol Physiol 36:312–318PubMedCrossRefGoogle Scholar
  15. 15.
    Xia Y, Karmazyn M (2004) Obligatory role for endogenous endothelin in mediating the hypertrophic effects of phenylephrine and angiotensin II in neonatal rat ventricular myocytes: evidence for two distinct mechanisms for endothelin regulation. J Pharmacol Exp Ther 310:43–51PubMedCrossRefGoogle Scholar
  16. 16.
    Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M (2003) The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res 93:277–279PubMedCrossRefGoogle Scholar
  17. 17.
    Gan XT, Chakrabarti S, Karmazyn M (2003) Increased endothelin-1 and endothelin receptor expression in myocytes of ischemic and reperfused rat hearts and ventricular myocytes exposed to ischemic conditions and its inhibition by nitric oxide generation. Can J Physiol Pharmacol 81:105–113PubMedCrossRefGoogle Scholar
  18. 18.
    Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, Luo JD (2004) Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 110:1269–1275PubMedCrossRefGoogle Scholar
  19. 19.
    Abe Y, Ono K, Kawamura T, Wada H, Kita T, Shimatsu A, Hasegawa K (2007) Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation. Am J Physiol Heart Circ Physiol 292:H2387–H2396PubMedCrossRefGoogle Scholar
  20. 20.
    Madani S, De Girolamo S, Munoz DM, Li RK, Sweeney G (2006) Direct effects of leptin on size and extracellular matrix components of human pediatric ventricular myocytes. Cardiovasc Res 69:716–725PubMedCrossRefGoogle Scholar
  21. 21.
    Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N (2011) Obesity and risk of incident heart failure in older men with and without pre-existing coronary heart disease: does leptin have a role? J Am Coll Cardiol 58:1870–1877PubMedCrossRefGoogle Scholar
  22. 22.
    Parrinello G, Scaglione R, Pinto A, Corrao S, Cecala M, Di Silvestre G, Amato P, Licata A, Licata G (1996) Central obesity and hypertension: the role of plasma endothelin. Am J Hypertens 9:1186–1191PubMedCrossRefGoogle Scholar
  23. 23.
    Zalesin KC, Franklin BA, Miller WM, Peterson ED, McCullough PA (2008) Impact of obesity on cardiovascular disease. Endocrinol Metab Clin North Am 37:663–684PubMedCrossRefGoogle Scholar
  24. 24.
    Van der Heiden K, Cuhlmann S, le Luong A, Zakkar M, Evans (2010) PC Role of nuclear factor kappaB in cardiovascular health and disease. Clin Sci (Lond) 118:593–605CrossRefGoogle Scholar
  25. 25.
    Gutierrez SH, Kuri MR, del Castillo ER (2008) Cardiac role of the transcription factor NF-kappaB. Cardiovasc Hematol Disord 8:153–160CrossRefGoogle Scholar
  26. 26.
    Freund C, Schmidt-Ullrich R, Baurand A, Dunger S, Schneider W, Loser P, El-Jamali A, Dietz R, Scheidereit C, Bergmann MW (2005) Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo. Circulation 111:2319–2325PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta S, Purcell NH, Lin A, d Sen S (2002) Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy. J Cell Biol 159:1019–1028PubMedCrossRefGoogle Scholar
  28. 28.
    Frantz S, Fraccarollo D, Wagner H, Behr TM, Jung P, Angermann CE, Ertl G, Bauersachs J (2003) Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure. Cardiovasc Res 57:749–756PubMedCrossRefGoogle Scholar
  29. 29.
    Wong SC, Fukuchi M, Melnyk P, Rodger I, Giaid A (1998) Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure. Circulation 98:100–103PubMedGoogle Scholar
  30. 30.
    Kawano S, Kubota T, Monden Y, Tsutsumi T, Inoue T, Kawamura N, Tsutsui H, Sunagawa K (2006) Blockade of NF-kappaB improves cardiac function and survival after myocardial infarction. Am J Physiol Heart Circ Physiol 291:H1337–H1344PubMedCrossRefGoogle Scholar
  31. 31.
    Brasier AR, Jamaluddin M, Han Y, Patterson C, Runge MS (2000) Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. Mol Cell Biochem 212:155–169PubMedCrossRefGoogle Scholar
  32. 32.
    Li XC, Zhuo JL (2008) Nuclear factor-kappaB as a hormonal intracellular signaling molecule: focus on angiotensin II-induced cardiovascular and renal injury. Curr Opin Nephrol Hypertens 17:37–43PubMedCrossRefGoogle Scholar
  33. 33.
    Celi A, Del Fiorentino A, Cianchetti S, Pedrinelli R (2008) Tissue factor modulation by Angiotensin II: a clue to a better understanding of the cardiovascular effects of renin-angiotensin system blockade? Endocr Metab Immune Disord Drug Targets 8:308–313PubMedCrossRefGoogle Scholar
  34. 34.
    Schorlemmer A, Matter ML, Shohet RV (2008) Cardioprotective signaling by endothelin. Trends Cardiovasc Med 18:233–239PubMedCrossRefGoogle Scholar
  35. 35.
    Zeidan A, Javadov S, Chakrabarti S, Karmazyn M (2008) Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and RhoA/ROCK-dependent p38 MAPK translocation to nuclei. Cardiovasc Res 77:64–72PubMedCrossRefGoogle Scholar
  36. 36.
    Skurk T, van Harmelen V, Blum WF, Hauner H (2005) Angiotensin II promotes leptin production in cultured human fat cells by an ERK1/2-dependent pathway. Obes Res 13:969–973PubMedCrossRefGoogle Scholar
  37. 37.
    Chandrasekar B, Valente AJ, Freeman GL, Mahimainathan L, Mummidi S (2006) Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun 339:956–963PubMedCrossRefGoogle Scholar
  38. 38.
    Perez DM, Papay RS, Shi T (2009) α1-Adrenergic receptor stimulates interleukin-6 expression and secretion through both mRNA stability and transcriptional regulation: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB. Mol Pharmacol 76:144–152PubMedCrossRefGoogle Scholar
  39. 39.
    Bkaily G, Avedanian L, Jacques D (2009) Nuclear membrane receptors and channels as targets for drug development in cardiovascular diseases. Can J Physiol Pharmacol 87:108–119PubMedCrossRefGoogle Scholar
  40. 40.
    Bkaily G, Avedanian L, Al-Khoury J, Provost C, Nader M, D’Orleans-Juste P, Jacques D (2011) Nuclear membrane receptors for ET-1 in cardiovascular function. Am J Physiol Regul Integr Comp Physiol 300:R251–R263PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Venkatesh Rajapurohitam
    • 1
  • Ana Kilic
    • 1
    • 2
  • Sabzali Javadov
    • 1
    • 3
  • Morris Karmazyn
    • 1
  1. 1.Department of Physiology & PharmacologyUniversity of Western OntarioLondonCanada
  2. 2.Institute of Pharmacology and Toxicology, Biomedical CenterUniversity of BonnBonnGermany
  3. 3.Department of Physiology, School of MedicineUniversity of Puerto RicoSan JuanUSA

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