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Tocotrienols confer resistance to ischemia in hypercholesterolemic hearts: insight with genomics

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Abstract

Most clinical trials with vitamin E could not lower cholesterol and thus, have been deemed unsuccessful. Recently, tocotrienols, isomers of vitamin E have been found to lower LDL levels. To explore if tocotrienols could be the drug target for vitamin E, rabbits were kept on cholesterol diet for 60 days supplemented with tocotrienol-α, tocotrienol-δ, and tocotrienol-γ for the last 30 days. The serum cholesterol levels (in mmol/l) were 24.4 (tocotrienol-α), 34.9 (tocotrienol-δ), 19.8 (tocotrienol-γ) vs. 39.7 (control). Left ventricular function including aortic flow and developed pressure exhibited significantly improved recovery with tocotrienol-γ and -α, but not with tocotrienol-δ. The myocardial infarct size showed a similar pattern: 33% (tocotrienol-α), 23% (tocotrienol-γ), and 47% (tocotrienol-δ). To examine the molecular mechanisms of cardioprotective effects, gene expression profile was determined using Atlas 1.2/1.2II followed by determination of gene profiles using PedQuest 8.3 software. Based on genomic profiles, the following cholesterol-related proteins were examined: FABP, TGF-β (cholesterol suppresses TGF-β), ET-1 (increased by hypercholesterolemia), SPOT 14 (linked with hypercholesterolemia), and matrix metalloproteinase (MMP) 2 and MMP9 (cholesterol regulates MMP2 and MMP9 expression) in the heart. Consistent with the cardioprotective effects of tocotrienol-α and -γ, these two isomers reduced ET-1, decreased MMP2 and MM9, increased TGF-β and reduced SPOT 14, while tocotrienol-δ had no effects. The results of the present study demonstrate that the two isomers of tocotrienols, α and γ, render the hypercholesterolemic hearts resistant to ischemic reperfusion injury by lowering several hypercholesterolemic proteins including MMP2, MMP9, ET-1, and SPOT 14 and upregulating TGF-β.

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References

  1. Qureshi A, Bradlow BA, Salser WA, Brace LD (1997) Novel tocotrienols of rice bran modulate cardiovascular disease risk parameters of hypercholesterolemic humans. J Nutr Biochem 8:290–298

    Article  CAS  Google Scholar 

  2. Khor HT, Chieng DY, Ong KK (1995) Tocotrienols inhibit liver HMG CoA reductase activity in the guinea pig. Nutr Res 15:537–544

    Article  CAS  Google Scholar 

  3. Watkins T, Lenz P, Gapor A, Struck M, Tomeo A, Bierenbaum M (1993) Gamma-tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Lipids 28:1113–1118

    Article  PubMed  CAS  Google Scholar 

  4. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ (1993) Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 268:11230–11238

    PubMed  CAS  Google Scholar 

  5. Vasanthi HR, Parameswari RP, Das DK (2011) Multifaceted role of tocotrienols in cardioprotection supports their structure: function relation. Genes Nutr. doi:10.1007/s12263-011-0227-9

  6. Pearce BC, Parker RA, Deason ME (1992) Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthelene analogues of the tocotrienols. J Med Chem 37:526–541

    Article  Google Scholar 

  7. Pearce BC, Parker RA, Deason ME (1992) Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem 35:3595–3606

    Article  PubMed  CAS  Google Scholar 

  8. Neely JR, Liebermeister H, Battersby EJ, Morgan HE (1967) Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol 212:804–814

    PubMed  CAS  Google Scholar 

  9. Juhasz B, Der P, Turoczi T, Bacskay I, Varga E, Tosaki A (2004) Preconditioning in intact and previously diseased myocardium: laboratory or clinical dilemma? Antioxidant Redox Signal 6:325–333

    Article  CAS  Google Scholar 

  10. Hamilton KL, Lin L, Wang Y, Knowlton AA (2007) Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS genes expression. Physiol Genomics 32:254–263

    Article  PubMed  Google Scholar 

  11. Skavdahl M, Steenbergen C, Clark J, Myers P, Demianenko T, Mao L, Rockman HA, Korach KS, Murphy E (2005) Estrogen receptor beta mediates male-female differences in the development of pressure overload hypertrophy. Am J Physiol 288:H469

    CAS  Google Scholar 

  12. Storch J, Thumser AE (2010) Tissue-specific functions in the fatty acid-binding protein family. J Biol Chem 285:32679–32683

    Article  PubMed  CAS  Google Scholar 

  13. Knowlton AA, Burrier RE, Brecher P (1989) Rabbit heart fatty acid binding protein: isolation, characterization, and application of a monoclonal antibody. Circ Res 65:981–988

    PubMed  CAS  Google Scholar 

  14. Binas B, Danneberg H, McWhir J, Mullins L, Clark JA (1999) Requirement for the heart-type fatty acid binding protein in cardiac fatty acid utilization. FASEB J 13:805–812

    PubMed  CAS  Google Scholar 

  15. Schaap FG, Binas B, Danneberg H, Van der Vusse GJ, Glatz JF (1999) Impaired long-chain fatty acid utilization by cardiac myocytes isolated from mice lacking the heart-type fatty acid binding protein gene. Circ Res 85:329–337

    PubMed  CAS  Google Scholar 

  16. ten Dijke P, Hill CS (2004) New insights into TGF-beta-smad signaling. Trends Biochem Sci 29:265–273

    Article  PubMed  CAS  Google Scholar 

  17. Moustakas A, Souchelnytskyi S, Heldin CH (2001) Smad regulation in TGF-beta signal transduction. J Cell Sci 114:4359–4369

    PubMed  CAS  Google Scholar 

  18. Mishra PK, Metreveli N, Tyagi SC (2010) MMP-9 gene ablation and TIMP-4 mitigate PAR-1-mediated cardiomyocyte dysfunction: a plausible role of dicer and miRNA. Cell Biochem Biophys 57:67–76

    Article  PubMed  CAS  Google Scholar 

  19. Baroncini LA, Nakao LS, Ramos SG, Filho AP, Murta LO Jr, Ingberman M, Tefé-Silva C, Précoma DB (2011) Assessment of MMP-9, TIMP-1, and COX-2 in normal tissue and in advanced symptomatic and asymptomatic carotid plaques. Thromb J 9:6

    Article  CAS  Google Scholar 

  20. Kandasamy AD, Chow AK, Ali MA, Schulz R (2010) Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix. Cardiovasc Res 85:413–423

    Article  PubMed  CAS  Google Scholar 

  21. Lehrke M, Greif M, Broedl UC, Lebherz C, Laubender RP, Becker A, von Ziegler F, Tittus J, Reiser M, Becker C, Göke B, Steinbeck G, Leber AW, Parhofer KG (2009) MMP-1 serum levels predict coronary atherosclerosis in humans. Cardiovasc Diabetol 8:50

    Article  PubMed  Google Scholar 

  22. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L (2003) Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 107:1579

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This study was supported in part by NIH HL 22559, HL 33889, and HL 34360.

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Authors and Affiliations

  1. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, 06030-1110, USA

    Somak Das, Subhendu Mukherjee, Istvan Lekli, Narasimman Gurusamy & Dipak K. Das

  2. Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary

    Istvan Lekli

  3. Center for Medicinal Food and Applied Nutrition, Department of Food Technology & Biochemical Engineering, Jadavpur University, Kolkata, India

    Jayeeta Bardhan, Utpal Raychoudhury, Runu Chakravarty & Sandip Banerji

  4. Molecular & Cellular Cardiology, University of California, Davis, CA, USA

    Anne A. Knowlton

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  1. Somak Das
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  2. Subhendu Mukherjee
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  10. Dipak K. Das
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Correspondence to Dipak K. Das.

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Das, S., Mukherjee, S., Lekli, I. et al. Tocotrienols confer resistance to ischemia in hypercholesterolemic hearts: insight with genomics. Mol Cell Biochem 360, 35–45 (2012). https://doi.org/10.1007/s11010-011-1041-9

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  • DOI: https://doi.org/10.1007/s11010-011-1041-9

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