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Reactivation of fatty acid oxidation by medium chain fatty acid prevents myocyte hypertrophy in H9c2 cell line

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Abstract

Metabolic shift is an important contributory factor for progression of hypertension-induced left ventricular hypertrophy into cardiac failure. Under hypertrophic conditions, heart switches its substrate preference from fatty acid to glucose. Prolonged dependence on glucose for energy production has adverse cardiovascular consequences. It was reported earlier that reactivation of fatty acid metabolism with medium chain triglycerides ameliorated cardiac hypertrophy, oxidative stress and energy level in spontaneously hypertensive rat. However, the molecular mechanism mediating the beneficial effect of medium chain triglycerides remained elusive. It was hypothesized that reduction of cardiomyocyte hypertrophy by medium chain fatty acid (MCFA) is mediated by modulation of signaling pathways over expressed in cardiac hypertrophy. The protective effect of medium chain fatty acid (MCFA) was evaluated in cellular model of myocyte hypertrophy. H9c2 cells were stimulated with Arginine vasopressin (AVP) for the induction of hypertrophy. Cell volume and secretion of brain natriuretic peptide (BNP) were used for assessment of cardiomyocyte hypertrophy. Cells were pretreated with MCFA (Caprylic acid) and metabolic modulation was assessed from the expression of medium-chain acyl-CoA dehydrogenase (MCAD), cluster of differentiation-36 (CD36) and peroxisome proliferator-activated receptor (PPAR)-α mRNA. The signaling molecules modified by MCFA was evaluated from protein expression of mitogen activated protein kinases (MAPK: ERK1/2, p38 and JNK) and Calcineurin A. Pretreatment with MCFA stimulated fatty acid metabolism in hypertrophic H9c2, with concomitant reduction of cell volume and BNP secretion. MCFA reduced activated ERK1/2, JNK and calicineurin A expression mediated by AVP. In conclusion, the beneficial effect of MCFA is possibly mediated by stimulation of fatty acid metabolism and modulation of MAPK and Calcineurin A.

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References

  1. Esposito G, Rapacciuolo A, Prasad SVN et al (2002) Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105:85–92. https://doi.org/10.1161/hc0102.101365

    Article  CAS  PubMed  Google Scholar 

  2. Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109:1580–1589. https://doi.org/10.1161/01.CIR.0000120390.68287.BB

    Article  PubMed  Google Scholar 

  3. Yusuf S, Sleight P, Pogue J et al (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145–153. https://doi.org/10.1056/NEJM200001203420301

    Article  CAS  PubMed  Google Scholar 

  4. Ingwall JS (2009) Energy metabolism in heart failure and remodelling. Cardiovasc Res 81:412–419. https://doi.org/10.1093/cvr/cvn301

    Article  CAS  PubMed  Google Scholar 

  5. Kolwicz SC, Olson DP, Marney LC et al (2012) Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res 111:728–738. https://doi.org/10.1161/CIRCRESAHA.112.268128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chess DJ, Khairallah RJ, O’Shea KM et al (2009) A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload. Am J Physiol Heart Circ Physiol 297:H1585–1593. https://doi.org/10.1152/ajpheart.00599.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Okere IC, Chess DJ, McElfresh TA et al (2005) High-fat diet prevents cardiac hypertrophy and improves contractile function in the hypertensive dahl salt-sensitive rat. Clin Exp Pharmacol Physiol 32:825–831. https://doi.org/10.1111/j.1440-1681.2005.04272.x

    Article  CAS  PubMed  Google Scholar 

  8. Duda MK, O’Shea KM, Lei B et al (2008) Low-carbohydrate/high-fat diet attenuates pressure overload-induced ventricular remodeling and dysfunction. J Card Fail 14:327–335. https://doi.org/10.1016/j.cardfail.2007.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ismael S, Purushothaman S, Harikrishnan VS, Nair RR (2015) Ligand specific variation in cardiac response to stimulation of peroxisome proliferator-activated receptor-alpha in spontaneously hypertensive rat. Mol Cell Biochem. https://doi.org/10.1007/s11010-015-2435-x

    Article  PubMed  Google Scholar 

  10. Saifudeen I, Subhadra L, Konnottil R, Nair RR (2017) Metabolic modulation by medium-chain triglycerides reduces oxidative stress and ameliorates CD36-mediated cardiac remodeling in spontaneously hypertensive rat in the initial and established stages of hypertrophy. J Card Fail 23:240–251. https://doi.org/10.1016/j.cardfail.2016.08.001

    Article  CAS  PubMed  Google Scholar 

  11. Molkentin JD, Lu J-R, Antos CL et al (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228

    Article  CAS  Google Scholar 

  12. Gutkind JS, Offermanns S (2009) A new Gq-initiated MAPK signaling pathway in the heart. Dev Cell 16:163–164. https://doi.org/10.1016/j.devcel.2009.01.021

    Article  CAS  PubMed  Google Scholar 

  13. Dorn GW, Brown JH (1999) Gq signaling in cardiac adaptation and maladaptation. Trends Cardiovasc Med 9:26–34. https://doi.org/10.1016/S1050-1738(99)00004-3

    Article  CAS  PubMed  Google Scholar 

  14. Zhu W, Tilley DG, Myers VD et al (2013) Arginine vasopressin enhances cell survival via a g protein-coupled receptor kinase 2/β-arrestin1/extracellular-regulated kinase 1/2–dependent pathway in H9c2 cells. Mol Pharmacol 84:227–235. https://doi.org/10.1124/mol.113.086322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. D’Angelo DD, Sakata Y, Lorenz JN et al (1997) Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA 94:8121–8126. https://doi.org/10.1073/pnas.94.15.8121

    Article  PubMed  Google Scholar 

  16. Wettschureck N, Rütten H, Zywietz A et al (2001) Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes. Nat Med 7:1236–1240. https://doi.org/10.1038/nm1101-1236

    Article  CAS  PubMed  Google Scholar 

  17. Hefti MA, Harder BA, Eppenberger HM, Schaub MC (1997) Signaling pathways in cardiac myocyte hypertrophy. J Mol Cell Cardiol 29:2873–2892. https://doi.org/10.1006/jmcc.1997.0523

    Article  CAS  PubMed  Google Scholar 

  18. Takeishi Y, Huang Q, Abe J et al (2001) Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch. J Mol Cell Cardiol 33:1637–1648. https://doi.org/10.1006/jmcc.2001.1427

    Article  CAS  PubMed  Google Scholar 

  19. Sadoshima J, Qiu Z, Morgan JP, Izumo S (1995) Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. The critical role of Ca(2+)-dependent signaling. Circ Res 76:1–15. https://doi.org/10.1161/01.res.76.1.1

    Article  CAS  PubMed  Google Scholar 

  20. De Windt LJ, Lim HW, Bueno OF et al (2001) Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98:3322–3327. https://doi.org/10.1073/pnas.031371998

    Article  PubMed  Google Scholar 

  21. Syed H, Gabriel C, Hae L et al (2001) Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103:670–677. https://doi.org/10.1161/01.CIR.103.5.670

    Article  Google Scholar 

  22. Irie H, Krukenkamp IB, Brinkmann JFF et al (2003) Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids. Proc Natl Acad Sci USA 100:6819–6824. https://doi.org/10.1073/pnas.1132094100

    Article  CAS  PubMed  Google Scholar 

  23. Brigadeau F, Gelé P, Wibaux M et al (2007) The PPARalpha activator fenofibrate slows down the progression of the left ventricular dysfunction in porcine tachycardia-induced cardiomyopathy. J Cardiovasc Pharmacol 49:408–415. https://doi.org/10.1097/FJC.0b013e3180544540

    Article  CAS  PubMed  Google Scholar 

  24. Ichihara S, Obata K, Yamada Y et al (2006) Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. J Mol Cell Cardiol 41:318–329. https://doi.org/10.1016/j.yjmcc.2006.05.013

    Article  CAS  PubMed  Google Scholar 

  25. Lebrasseur NK, Duhaney T-AS, De Silva DS et al (2007) Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. Hypertens Dallas Tex 1979(50):489–496. https://doi.org/10.1161/HYPERTENSIONAHA.107.092403

    Article  CAS  Google Scholar 

  26. Young ME, Laws FA, Goodwin GW, Taegtmeyer H (2001) Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem 276:44390–44395. https://doi.org/10.1074/jbc.M103826200

    Article  CAS  PubMed  Google Scholar 

  27. Purushothaman S, Sathik MM, Nair RR (2011) Reactivation of peroxisome proliferator-activated receptor alpha in spontaneously hypertensive rat: age-associated paradoxical effect on the heart. J Cardiovasc Pharmacol 58:254–262. https://doi.org/10.1097/FJC.0b013e31822368d7

    Article  CAS  PubMed  Google Scholar 

  28. Morgan EE, Rennison JH, Young ME et al (2006) Effects of chronic activation of peroxisome proliferator-activated receptor-alpha or high-fat feeding in a rat infarct model of heart failure. Am J Physiol Heart Circ Physiol 290:H1899–1904. https://doi.org/10.1152/ajpheart.01014.2005

    Article  CAS  PubMed  Google Scholar 

  29. Chess DJ, Lei B, Hoit BD et al (2008) Effects of a high saturated fat diet on cardiac hypertrophy and dysfunction in response to pressure overload. J Card Fail 14:82–88. https://doi.org/10.1016/j.cardfail.2007.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Okere IC, Young ME, McElfresh TA et al (1979) (2006) Low carbohydrate/high-fat diet attenuates cardiac hypertrophy, remodeling, and altered gene expression in hypertension. Hypertens Dallas Tex 48:1116–1123. https://doi.org/10.1161/01.HYP.0000248430.26229.0f

    Article  CAS  Google Scholar 

  31. Iemitsu M, Shimojo N, Maeda S et al (2008) The benefit of medium-chain triglyceride therapy on the cardiac function of SHRs is associated with a reversal of metabolic and signaling alterations. Am J Physiol Heart Circ Physiol 295:H136–144. https://doi.org/10.1152/ajpheart.01417.2006

    Article  CAS  PubMed  Google Scholar 

  32. Nguyen TD, Shingu Y, Amorim PA et al (2015) Triheptanoin alleviates ventricular hypertrophy and improves myocardial glucose oxidation in rats with pressure overload. J Card Fail 21:906–915. https://doi.org/10.1016/j.cardfail.2015.07.009

    Article  CAS  PubMed  Google Scholar 

  33. Hajri T, Ibrahimi A, Coburn CT et al (2001) Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. J Biol Chem 276:23661–23666. https://doi.org/10.1074/jbc.M100942200

    Article  CAS  PubMed  Google Scholar 

  34. Kimes BW, Brandt BL (1976) Properties of a clonal muscle cell line from rat heart. Exp Cell Res 98:367–381. https://doi.org/10.1016/0014-4827(76)90447-x

    Article  CAS  PubMed  Google Scholar 

  35. Watkins SJ, Borthwick GM, Arthur HM (2011) The H9C2 cell line and primary neonatal cardiomyocyte cells show similar hypertrophic responses in vitro. In Vitro Cell Dev Biol Anim 47:125–131. https://doi.org/10.1007/s11626-010-9368-1

    Article  CAS  PubMed  Google Scholar 

  36. Saeedi R, Saran VV, Wu SSY et al (2009) AMP-activated protein kinase influences metabolic remodeling in H9c2 cells hypertrophied by arginine vasopressin. Am J Physiol Heart Circ Physiol 296:H1822–1832. https://doi.org/10.1152/ajpheart.00396.2008

    Article  CAS  PubMed  Google Scholar 

  37. Brostrom MA, Reilly BA, Wilson FJ, Brostrom CO (2000) Vasopressin-induced hypertrophy in H9c2 heart-derived myocytes. Int J Biochem Cell Biol 32:993–1006. https://doi.org/10.1016/s1357-2725(00)00037-6

    Article  CAS  PubMed  Google Scholar 

  38. Chirinos JA, Sardana M, Oldland G et al (2018) Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure. ESC Heart Fail 5:911–919. https://doi.org/10.1002/ehf2.12319

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hupf H, Grimm D, Riegger GA, Schunkert H (1999) Evidence for a vasopressin system in the rat heart. Circ Res 84:365–370. https://doi.org/10.1161/01.res.84.3.365

    Article  CAS  PubMed  Google Scholar 

  40. Hiroyama M, Wang S, Aoyagi T et al (2007) Vasopressin promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor in neonatal mice. Eur J Pharmacol 559:89–97. https://doi.org/10.1016/j.ejphar.2006.12.010

    Article  CAS  PubMed  Google Scholar 

  41. Sung MM, Byrne NJ, Kim TT et al (2017) Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure. Am J Physiol Heart Circ Physiol 312:H552–H560. https://doi.org/10.1152/ajpheart.00626.2016

    Article  PubMed  Google Scholar 

  42. Adiga IK, Nair RR (2008) Multiple signaling pathways coordinately mediate reactive oxygen species dependent cardiomyocyte hypertrophy. Cell Biochem Funct 26:346–351. https://doi.org/10.1002/cbf.1449

    Article  CAS  PubMed  Google Scholar 

  43. Thibonnier M, Berti-Mattera LN, Dulin N et al (1999) Signal transduction pathways of the human V1-vascular, V2-renal, V3-pituitary vasopressin and oxytocin receptors. In: Urban IJA, Burbach JPH, De Wed D (eds) Progress in brain research. Elsevier, Amsterdam, pp 147–161

    Google Scholar 

  44. Mutlak M, Kehat I (2015) Extracellular signal-regulated kinases 1/2 as regulators of cardiac hypertrophy. Front Pharmacol. https://doi.org/10.3389/fphar.2015.00149

    Article  PubMed  PubMed Central  Google Scholar 

  45. Barger PM, Brandt JM, Leone TC et al (2000) Deactivation of peroxisome proliferator–activated receptor-α during cardiac hypertrophic growth. J Clin Invest 105:1723–1730

    Article  CAS  Google Scholar 

  46. Wang Y, Su B, Sah VP et al (1998) Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol Chem 273:5423–5426. https://doi.org/10.1074/jbc.273.10.5423

    Article  CAS  PubMed  Google Scholar 

  47. Zechner D, Thuerauf DJ, Hanford DS et al (1997) A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. J Cell Biol 139:115–127

    Article  CAS  Google Scholar 

  48. Wilkins BJ, Yan-Shan D, Bueno OF et al (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118. https://doi.org/10.1161/01.RES.0000109415.17511.18

    Article  CAS  PubMed  Google Scholar 

  49. Odle J (1997) New insights into the utilization of medium-chain triglycerides by the neonate: observations from a piglet model. J Nutr 127:1061–1067

    Article  CAS  Google Scholar 

  50. Hu FB, Stampfer MJ, Manson JE et al (1999) Dietary saturated fats and their food sources in relation to the risk of coronary heart disease in women. Am J Clin Nutr 70:1001–1008

    Article  CAS  Google Scholar 

  51. Labarthe F (2004) Fatty acid oxidation and its impact on response of spontaneously hypertensive rat hearts to an adrenergic stress: benefits of a medium-chain fatty acid. AJP Heart Circ Physiol 288:H1425–H1436. https://doi.org/10.1152/ajpheart.00722.2004

    Article  Google Scholar 

  52. Allard MF, Parsons HL, Saeedi R et al (2007) AMPK and metabolic adaptation by the heart to pressure overload. Am J Physiol Heart Circ Physiol 292:H140–148. https://doi.org/10.1152/ajpheart.00424.2006

    Article  CAS  PubMed  Google Scholar 

  53. el Alaoui-Talibi Z, Landormy S, Loireau A, Moravec J (1992) Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts. Am J Physiol 262:H1068–H1074

    PubMed  Google Scholar 

  54. Behrend AM, Harding CO, Shoemaker JD et al (2012) Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation. Mol Genet Metab 105:110–115. https://doi.org/10.1016/j.ymgme.2011.09.030

    Article  CAS  PubMed  Google Scholar 

  55. Finck BN, Han X, Courtois M et al (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA 100:1226–1231. https://doi.org/10.1073/pnas.0336724100

    Article  CAS  PubMed  Google Scholar 

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  1. Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, 695 011, India

    Saifudeen Ismael & R. Renuka Nair

  2. Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA

    Saifudeen Ismael

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Saifudeen Ismael was a recipient of Senior Research Fellowship from the Indian Council of Medical Research, India. No conflict of interest to be declared.

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Ismael, S., Nair, R.R. Reactivation of fatty acid oxidation by medium chain fatty acid prevents myocyte hypertrophy in H9c2 cell line. Mol Cell Biochem 476, 483–491 (2021). https://doi.org/10.1007/s11010-020-03925-1

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