Abstract
Genetic mapping of the progeny of an F2 intercross between WKY and WKHA rats had previously allowed us to detect male-specific linkage between locus Cm24 and left ventricular mass index (LVMI). By further expanding that analysis, we detected additional loci that were all linked to LVMI in a sex-specific manner despite their autosomal location. In males, we detected one additional locus (Lvm8) on Chromosome 5 (LOD = 3.4), the two loci Lvm13 (LOD = 4.5) and Lvm9 (LOD = 2.8) on Chromosome 17, and locus Lvm10 (LOD = 4.2) on Chromosome 12. The locus Lvm13 had the same boundaries as locus Cm26 previously reported by others using a different cross. None of these loci showed linkage to LVM in females. In contrast, we identified in females the novel locus Lvm11 on Chromosome 15 (LOD = 2.8) and locus Lvm12 (LOD = 2.7) that had the same boundaries on Chromosome 3 as locus Cm25 detected previously by others using a cross of other normotensive strains. In prepubertal males, there were no differences in the width of cardiomyocytes from WKY and WKHA rats, but cardiomyocytes from WKHA became progressively wider than that of WKY as sexual maturation progressed. Altogether, these results provide evidence that distinct genes may influence LVMI of rats in a sex-dependent manner, maybe by involving sex-specific interactions of sex steroids with particular genes involved in the determination of LVMI and/or cardiomyocyte width.
Similar content being viewed by others
References
Aiello EA, Villa-Abrille MC, Escudero EM, Portiansky EL, Perez NG, et al. (2004) Myocardial hypertrophy of normotensive Wistar-Kyoto rats. Am J Physiol 286:H1229–H1235
Altmüller J, Palmer LJ, Fischer G, Scherb H, Wjst M (2001) Genomewide scans of complex human diseases: true linkage is hard to find. Am J Hum Genet 69:936–950
Babiker FA, De Windt LJ, van Eickels M, Thijssen V, Bronsaer RJP, et al. (2004) 17β-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway. Circulation 109:269–276
Bilusic M, Bataillard A, Tschannen MR, Gao L, Barreto NE, et al. (2004) Mapping the genetic determiants of hypertension, metabolic diseases, and related phenotypes in the Lyon hypertensive rat. Hypertension 44:695–701
Boheler KR, Volkova M, Morrell C, Garg R, Zhu Y, et al. (2003) Sex- and age-dependent human transcriptome variability: implications for chronic heart failure. Proc Natl Acad Sci U S A 100:2754–2759
Boutin-Ganache I, Raposo M, Raymond M, Deschepper CF (2001) M13-tailed primers improve the readibility and usability of microsatellite analyses performed with two different allele-sizing methods. Biotechniques 31:24–26
Boutin-Ganache I, Picard S, Deschepper CF (2002) Distinct gene-sex interactions regulate adult rat cardiomyocyte width and length independently. Physiol Genomics 12:61–67
Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971
Cicila GT, Dukhanina OI, Kurtz T, Walder R, Garrett MR, et al. (1997) Blood pressure and survival on a chromosome 7 congenic strain bred from Dahl rats. Mamm Genome 8:896–902
Cicila GT, Choi C, Dene H, Lee SJ, Rapp JP (1999) Two blood pressure/cardiac mass quantitative loci on chromosome 3 in Dahl rats. Mamm Genome 10:112–116
Cohn JN (1998) Arteries, myocardium, blood pressure and cardiovascular risk: towards a revised definition of hypertension. J Hypertens 16:2117–2124
Colecraft HM, Alseikhan B, Takahashi SX, Chaudhuri D, Mittman S, et al. (2002) Novel functional properties of Ca2+ channel β subunits revealed by their expression in adult rat heart cells. J Physiol 541:435–452
Courvoisier H, Bihoreau M-T, Gauguier D, Plomion C, Mormède P, et al. (1997) Integrated genetic mapping of 64 rat microsatellite markers from different sources. Mamm Genome 8:282–283
Darvasi A, Soller M (1992) Selective genotyping for determination of linkage between a marker locus and a quantitative trait locus. Theor Appl Genet 85:353–359
de Simone G, Verdecchia P, Pede S, Gorini M, Maggioni AP (2002) Prognosis of inappropriate left ventricular mass in hypertension. The MAVI study. Hypertension 40:470–476
Deschepper CF, Masciotra S, Zahabi A, Boutin-Ganache I, Picard S, et al. (2001) Functional alterations of the Nppa promoter are linked to cardiac ventricular hypertrophy in WKY/WKHA rat crosses. Circ Res 88:222–227
Deschepper CF, Picard S, Thibault G, Touyz R, Rouleau JL (2002) Characterization of left ventricular myocardium, isolated cardiomyocytes and blood pressure in WKHA and WKY rats. Am J Physiol 82:H149–H155
Devereux RB, de Simone G, Ganau A, Roman MJ (1994) Left ventricular hypertrophy and geometric remodeling in hypertension: stimuli, functional consequences and prognostic implications. J Hypertens 12 (Suppl. 10):S117–S127
Du X-J (2004) Gender modulates cardiac pheotype development in genetically modified mice. Cardiovasc Res 63:510–519
Frey N, McKinsey TA, Olson EN (2000) Decoding calcium signals involved in cardiac growth and function. Nat Med 6:1221–1227
Garrett MR, Dene H, Rapp JP (2003) Time-course genetic analysis of albuminuria in Dahl salt-sensitive rats on low-salt diet. J Am Soc Nephrol 14:1175–1187
Garrett MR, Saad Y, Dene H, Rapp JP (2005) Blood pressure QTL that differentiate Dahl salt-sensitive and spontaneously hypertensive rats. Physiol Genomics 29:33–38
Gerdes AM (1992) The use of isolated myocytes to evaluate myocardial remodeling. Trends Cardiovasc Med 2:152–155
Golden KL, Marsh JD, Jiang Y (2004) Testosterone regulates mRNA levels of calcium regulatory proteins in cardiac myocytes. Horm Metab Res 36:197–202
Haley CS, Knott SA (1992) Simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69:315–324
Heling A, Zimmermann R, Kostin S, Maeno Y, Hein S, et al. (2000) Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circ Res 86:846–853
Hendley ED, Ohlsson WG (1991) Two new inbred rat strains derived from SHR: WKHA, hyperactive, and WKHT, hypertensive, rats. Am J Physiol 261:H583–H589
Holtwick R, van Eickels M, Skryabin BV, Baba HA, Bubikat A, et al. (2003) Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl-cyclase-A. J Clin Invest 111:1399–1407
Innes BA, McLaughlin MG, Kapuscinski MK, Jacob HJ, Harrap SB (1998) Independent genetic susceptibility to cardiac hypertrophy in inherited hypertension. Hypertension 31:741–746
Kato N, Tamada T, Nabika T, Ueno K, Gotoda T, et al. (2000) Identification of quantitative trait loci for serum cholesterol levels in stroke-prone hypertensive rats. Arterioscler Thromb Vasc Biol 20:223–229
Kato N, Hyne G, Bihoreau M-T, Ganguier D, Lathrop GM, et al. (2005) Complete genome searches for quantitative trait loci controlling blood pressure and related traits in four segregating populations derived from Dahl hypertensive rats. Mamm Genome 10:259–265
Korstanje R, Li R, Howard T, Kelmenson P, Marshall J, et al. (2004) Influence of sex and diet on quantitative trait loci for HDL-cholesterol levels in a SM/J by NZB/BlNJ intercross population. J Lipid Res 45:881–888
Kovács P, Voigt B, Klöting I (1998) Congenic strain confirms putative quantitative trait locus for body weight in the rat. Mamm Genome 9:294–296
Kuribayashi T, Mizuta T, Shimoo K, Kubota H, Katsume H, et al. (1988a) Spontaneously occurring hypertrophic cardiomyopathy in the rat. II. Distribution of, and correlations between, various cardiac abnormalities in the WKY/NCrj and its related strains. Jpn Circ J 52:1156–1170
Kuribayashi T, Mizuta T, Shimoo K, Kubota Y, Katsume H, et al. (1988b) Spontaneously occurring hypertrophic cardiomyopathy in the rat. I. Pathologic features. Jpn Circ J 51:573–588
Lander ES, Kruglyak L (1995) Genetic dissection of compex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247
Leinwand LA (2003) Sex is a potent modifier of the cardiovascular system. J Clin Invest 112:302–307
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 322:1561–1566
Li Y, Kishimoto I, Saito Y, Harada M, Kuwahara K, et al. (2004) Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology 145:951–958
Liu QY, Karpinski E, Pang PK (1994) The L-type calcium channel current is increased by alpha-1 adrenoceptor activation in neonatal rat ventricular cells. J Pharmacol Exp Ther 271:935–943
Manly KF, Olson JM (1999) Overview of QTL mapping software and introduction to Map Manager QT. Mamm Genome 10:327–334
Moreno C, Dumas P, Kaldunski ML, Tonellato PJ, Greene AS, et al. (2003) Genomic map of cardiovascular phenotypes of hypertension in female Dahl S rats. Physiol Genomics 15:243–257
Nunez DJR, Clifford CP, Al-Mahdawi S, Dutka D (1996) Hypertensive cardiac hypertrophy—is genetic variance the missing link? Br J Clin Pharmacol 42:107–117
Pfeffer MA, Pfeffer JM, Dunn FG, Nishiyama K, Tsuchiya M, et al. (1979) Natural biventricular hypertrophy in normotensive rats. I. Physical and hemodynamic characteristics. Am J Physiol 236:H640–H643
Sebkhi A, Zhao L, Lu L, Haley CS, Nunez DJR, et al. (1999) Genetic determination of cardiac mass in normotensive rats. Results from an F344 × WKY cross. Hypertension 33:949–953
Sehl PD, Tai JT, Hillan KJ, Brown LA, Goddard A, et al. (2000) Application of cDNA microarrays in determining molecular phenotype in cardiac growth, development, and response to injury. Circulation 101:1990–1999
Sei CA, Irons CE, Sprenkle AB, McDonough PM, Brown JH, et al. (1991) The α-adrenergic stimulation of atrial natriuretic factor expression in cardiac myocytes requires calcium influx, protein kinase C, and calmodulin-regulated pathways. J Biol Chem 266:15910–15916
Sharp A, Mayet J (2002) Regression of left ventricular hypertrophy: hoping for a longer life. J Renin Angiotensin Aldosterone Syst 3:141–144
Siegel AK, Planert M, Rademacher S, Mehr AP, Kossmehl P, et al. (2003) Genetic loci contribute to the progression of vascular and cardiac hypertrophy in salt-sensitive spontaneous hypertension. Arterioscler Thromb Vasc Biol 23:1211–1217
Slama M, Susic D, Varagic J, Frohlich ED (2002) High rate of ventricular septal defects in WKY rats. Hypertension 40:175–178
Stoll M, Cowley AW Jr, Tonellato PJ, Greene AS, Kaldunski ML, et al. (2001) A genomic-systems biology map for cardiovascular function. Science 294:1723–1726
Touyz RM, Fareh J, Thibault G, Schiffrin EL (1996) Intracellular Ca2+ modulation by angiotensin II and endothelin-1 in cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats. Hypertension 28:797–805
Tsujita Y, Iwai N, Tamaki S, Nakamura Y, Nishimura M, et al. (2000) Genetic mapping of quantitative trait loci influencing left ventricular mass in rats. Am J Physiol 279:H2062–H2067
Verhaaren HA, Schieken RM, Mosteller M, Hewitt JK, Eaves LJ, et al. (1991) Bivariate genetic analysis of left ventricular mass and weight in pubertal twins (the Medical College of Wisconsin twin study). Am J Cardiol 68:661–668
Visscher PM, Thompson R, Haley CS (1996) Confidence intervals in QTL mapping by bootstrapping. Genetics 143:1013–1020
Zahabi A, Picard S, Fortin N, Reudelhuber TL, Deschepper CF (2003) Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse hearts. J Biol Chem 278:47694–47699
Zhang S, Hiraoka M, Hirano Y (1998) Effects of α1-adrenergic stimulation on L-type Ca2+ current in rat ventricular myocytes. J Mol Cell Cardiol 30:1955–1965
Zhang R, Crump J, Reisin E (2003) Regression of left ventricular hypertrophy is a key goal of hypertension management. Curr Hypertens Rep 5:301–308
Zou Y, Yamazaki T, Nakagawa K, Yamada H, Iriguchi N, et al. (2002) Continuous blockade of L-type Ca2+ channels suppresses activation of calcineurin and development of cardiac hypertrophy in spontaneously hypertensive rats. Hypertens Res 25:117–124
Acknowledgments
This work was supported by the NIH/NHLBI grant HL69122 (to CFD) and by a Group Grant of the Canadian Institutes for Health Research (CIHR) to the IRCM Multidisciplinary Research Group in Hypertension.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Llamas, B., Jiang, Z., Rainville, ML. et al. Distinct QTLs are linked to cardiac left ventricular mass in a sex-specific manner in a normotensive inbred rat intercross. Mamm Genome 16, 700–711 (2005). https://doi.org/10.1007/s00335-005-0041-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-005-0041-z