Molecular and Cellular Biochemistry

, Volume 314, Issue 1–2, pp 37–43 | Cite as

Abnormal Igf2 gene in Prague hereditary hypertriglyceridemic rats: its relation to blood pressure and plasma lipids

  • Michaela Kadlecová
  • Zdenka Dobešová
  • Josef Zicha
  • Jaroslav KunešEmail author


Prague hypertriglyceridemic (HTG) rats represent a suitable model of metabolic syndrome. We have established the set of F2 hybrids derived from HTG and Lewis progenitors to investigate the relationship between respective polymorphism(s) of Igf2 gene and blood pressure (BP) or other cardiovascular phenotypes. HTG rats had elevated systolic BP and plasma triglycerides but lower plasma cholesterol compared to Lewis rats of both genders. In males, there was higher mean arterial pressure, diastolic BP and relative heart weight in HTG than in Lewis rats. The results obtained in the total population of F2 hybrids indicated strong segregation of Igf2 genotype with plasma triglycerides. There was no segregation of Igf2 genotype with any BP component except BP changes occurring after the blockade of either renin–angiotensin system (RAS) or NO synthase. When F2 population was analyzed according to gender, male F2 progeny homozygous for HTG Igf2 allele had significantly higher plasma triglycerides and greater BP changes after NO synthase blockade than those homozygous for Lewis allele. On the contrary, male F2 progeny homozygous for HTG Igf2 allele had significantly lower plasma cholesterol and smaller BP changes after RAS blockade. PCR analysis of Igf2 gene by using of microsatelite D1Mgh22 has shown polymorphism between HTG and Lewis rats. Sequence analysis of cDNA revealed insertion of 14 nucleotides in HTG gene. In conclusion, polymorphism in Igf2 gene may be responsible for differences in lipid metabolism between HTG and Lewis rats. It remains to determine how these abnormalities could be involved in BP regulation by particular vasoactive systems.


Plasma cholesterol Triglycerides Polymorphism Genetic determinants Hypertension F2 hybrids Metabolic syndrome 



This work was supported by AV0Z 5110509, Centre for Cardiovascular Research (1M0510), and GA CR grant 305/08/0139.


  1. 1.
    Sarzani R, Brecher P, Chobanian AV (1989) Growth factor expression in aorta of normotensive and hypertensive rats. J Clin Invest 83:1404–1408PubMedCrossRefGoogle Scholar
  2. 2.
    Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ (2002) Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet 359:1740–1745PubMedCrossRefGoogle Scholar
  3. 3.
    Holt RI, Simpson HL, Sonksen PH (2003) The role of the growth hormone insulin-like growth factor axis in glucose homeostasis. Diabet Med 20:3–15PubMedCrossRefGoogle Scholar
  4. 4.
    Hunt KJ, Lukanova A, Rinaldi S, Lundin E, Norat T, Palmqvist R, Stattin P, Riboli E, Hallmans G, Kaaks R (2006) A potential inverse association between insulin-like growth factor-I and hypertension in a cross-sectional study. Ann Epidemiol 16:563–571PubMedCrossRefGoogle Scholar
  5. 5.
    Copeland KC, Nair KS (1994) Recombinant human insulin-like growth factor-I increases forearm blood flow. J Clin Endocrinol Metab 79:230–232PubMedCrossRefGoogle Scholar
  6. 6.
    Wu H-Y, Young YJ, Yue C-J, Kuang-Yuh C, Hsueh WA, Chan TM (1994) Endothelial-dependent vascular effects of insulin and insulin-like growth factor-I in the perfused rat mesenteric artery and aortic ring. Diabetes 43:1027–1032PubMedCrossRefGoogle Scholar
  7. 7.
    Conti E, Carozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, Andreotti F (2004) Insulin-like growth factor-1 as a vascular protective factor. Circulation 110:2260–2265PubMedCrossRefGoogle Scholar
  8. 8.
    Schini-Kerth VB (1999) Dual effects of insulin-like growth factor-1 on the constitutive and inducible nitric oxide (NO) synthase-dependent formation of NO in vascular cells. J Endocrinol Invest 22(Suppl):82–88PubMedGoogle Scholar
  9. 9.
    Vecchione C, Colella S, Fratta L, Gentile MT, Selvetella G, Frati G, Trimarco B, Lembo G (2001) Impaired insulin-like growth factor-I vasorelaxant effects in hypertension. Hypertension 37:1480–1485PubMedGoogle Scholar
  10. 10.
    te Velde SJ, van Rossum EFC, Voorhoever PG, Twisk JWR, Delemarre van de Wal HA, Stehouwer CDA, van Mechelen W, Lamberts SWJ, Kemper HCG (2005) An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36. BMC Endocr Disord 5:5PubMedCrossRefGoogle Scholar
  11. 11.
    Vrána A, Kazdová L (1990) The hereditary hypertriglyceridemic nonobese rat: an experimental model of human hypertriglyceridemia. Transplant Proc 22:2579PubMedGoogle Scholar
  12. 12.
    Zicha J, Pecháňová O, Čačányiová S, Cebová M, Kristek F, Török J, Šimko F, Dobešová Z, Kuneš J (2006) Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome? Physiol Res 55(Suppl 1):S49–S63PubMedGoogle Scholar
  13. 13.
    Štolba P, Dobešová Z, Hušek P, Opltová H, Zicha J, Vrána A, Kuneš J (1992) The hypertriglyceridemic rat as a genetic model of hypertension and diabetes. Life Sci 51:733–740PubMedCrossRefGoogle Scholar
  14. 14.
    Devynck MA, Kuneš J, Le Quan Sang KH, Zicha J (1998) Membrane microviscosity and plasma triacylglycerols in the rat. Clin Sci 94:79–85PubMedGoogle Scholar
  15. 15.
    Kadlecová M, Hojná S, Bohuslavová R, Hubáček JA, Zicha J, Kuneš J (2006) Apolipoprotein A5 and hypertriglyceridemia in Prague hypertriglyceridemic rats. Physiol Res 55:373–379PubMedGoogle Scholar
  16. 16.
    Kuneš J, Dobešová Z, Zicha J (1995) High blood pressure of hypertriglyceridaemic rats is related to metabolic disturbances. Physiol Res 44:421–425PubMedGoogle Scholar
  17. 17.
    Kadlecová M, Čejka J, Zicha J, Kuneš J (2004) Does Cd36 gene play a key role in disturbed glucose and fatty acid metabolism in Prague hypertensive hypertriglyceridemic rats? Physiol Res 53:265–271PubMedGoogle Scholar
  18. 18.
    Zicha J, Dobešová Z, Kuneš J (1997) Plasma triglycerides and red cell ion transport alterations in genetically hypertensive rats. Hypertension 30:636–640PubMedGoogle Scholar
  19. 19.
    Kuneš J, Dobešová Z, Zicha J (2002) Altered balance of main vasopressor and vasodepressor systems in rats with genetic hypertension and hypertriglyceridaemia. Clin Sci 102:269–277PubMedCrossRefGoogle Scholar
  20. 20.
    Ueno T, Tremblay J, Kuneš J, Zicha J, Dobešová Z, Pausová Z, Deng AY, Sun Y-L, Jacob H, Hamet P (2003) Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems. J Mol Med 81:51–60PubMedGoogle Scholar
  21. 21.
    Ueno T, Tremblay J, Kuneš J, Zicha J, Dobešová Z, Pausová Z, Deng AY, Sun Y-L, Jacob H, Hamet P (2004) Rat model of familial combined hyperlipidemia as a result of comparative mapping. Physiol Genomics 17:38–47PubMedCrossRefGoogle Scholar
  22. 22.
    Kovacs P, Voigt B, Klöting I (1997) Novel quantitative trait loci for blood pressure and related traits on rat chromosomes 1, 10 and 18. Biochem Biophys Res Commun 235:343–348PubMedCrossRefGoogle Scholar
  23. 23.
    Saad Y, Garrett MR, Lee SJ, Dene H, Rapp JP (1999) Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains. Physiol Genomics 1:119–125PubMedGoogle Scholar
  24. 24.
    St Lezin E, Griffin KA, Picken M, Churchill MC, Churchill PC, Kurtz TW, Liu W, Wang N, Kren V, Zidek V, Pravenec M, Bidani AK (1999) Genetic isolation of a chromosome 1 region affecting susceptibility to hypertension-induced renal damage in the spontaneously hypertensive rat. Hypertension 34:187–191PubMedGoogle Scholar
  25. 25.
    Lee S-D, Chu C-H, Huang E-J, Lu M-C, Liu J-Y, Liu C-J, Hsu H-H, Lin JA, Kuo W-W, Huang C-Y (2006) Roles of insulin-like growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation. Am J Physiol 291:E306–E314Google Scholar
  26. 26.
    Sowers JR (1997) Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension 29:691–699PubMedGoogle Scholar
  27. 27.
    Kluge A, Zimmermann R, Munkel B, Verdouw PD, Schaper J, Schaper W (1995) Insulin-like growth factor II is a experimental stress inducible gene in a porcine model of brief coronary occlusion. Cardiovasc Res 29:708–716PubMedCrossRefGoogle Scholar
  28. 28.
    Kovacs P, van den Brandt J, Klöting I (1998) Effects of quantitative trait loci for lipid phenotypes in the rat are influenced by age. Clin Exp Pharmacol Physiol 25:1004–1007PubMedCrossRefGoogle Scholar
  29. 29.
    Aouizerat BE, Allayee H, Cantor RM, Davis RC, Lanning CD, Wen PZ, Dallinga-Thie GM, de Bruin TW, Rotter JI, Lusis AJ (1999) A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11. Am J Hum Genet 65:397–412PubMedCrossRefGoogle Scholar
  30. 30.
    Paolisso G, Tagliamonte MR, Rizzo MR, Giugliano D (1999) Advancing age and insulin resistance: new facts about an ancient history. Eur J Clin Invest 29:758–769PubMedCrossRefGoogle Scholar
  31. 31.
    DeChiara TM, Robertson EJ, Efstratiadis A (1991) Parental imprinting of the mouse insuline-like growth factor II gene. Cell 64:849–859PubMedCrossRefGoogle Scholar
  32. 32.
    Eggenschwiler J, Ludwig T, Fisher P, Leighton PA, Tilghman SM, Efstratiadis A (2007) Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes. Genes Dev 11:3128–3142CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Michaela Kadlecová
    • 1
  • Zdenka Dobešová
    • 1
  • Josef Zicha
    • 1
  • Jaroslav Kuneš
    • 1
    Email author
  1. 1.Institute of PhysiologyAcademy of Sciences of the Czech Republic and Cardiovascular Research CenterPrague 4Czech Republic

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