The hypertrophic heart rat (HHR) was derived from the spontaneously hypertensive rat of the Okamoto strain and develops cardiac hypertrophy in the absence of hypertension. The genetic basis of this hypertrophy is unknown. Therefore, we compared gene expression profiles in the left ventricular myocardium of young (8-10 weeks of age) and old (38-50 weeks) HHR with rats from an age-matched control strain, the normal heart rat (NHR). cDNA microarrays (National Institute of Aging [NIA], 15,247 clones) were used to evaluate gene expression in cardiac-derived Cy3 and Cy5 labeled cDNA. M values (log2[Cy5/Cy3]) were obtained and significant differential expression was identified using an empirical Bayesian approach with specific results verified using real-time PCR. Compared with NHR, HHR cardiac weight index (heart weight/ body weight) was significantly elevated at both ages (young: 5.5 +/- 0.5 vs. 3.9 +/- 0.2; old: 4.2 +/- 0.3 vs. 3.4 +/- 0.2 mg/g; p < 0.05) with no difference in body weight or in tail-cuff blood pressure detected between the strains at either age. Differential expression was observed in 65 and 390 clones in young and old HHR, respectively, with more genes exhibiting down-regulation than up-regulation in both instances (young: down 44 vs. up 21; old: down 292 vs. up 98). Our data suggest a role for the Ras/mitogen-activated protein kinase (MAPK) signaling pathway and the tumor necrosis factor (TNF) receptor-mediated activation of nuclear factor-kappaB (NF-kappaB) in the etiology of cardiac enlargement in the HHR. These findings support the candidature of previously identified cardiotrophic agents in contributing to the cardiac enlargement in the normotensive HHR, and also identify novel genetic factors which may be involved in the genesis of primary cardiac hypertrophy.