Cardiac hypertrophy is a hallmark of aging. Hypertrophied hearts of aged mammals resemble those of hypertensive younger rats in many respects, including changes in expression of a number of specific genes. It was not known, however, whether adrenergic receptor mediated hypertrophy shared common features of gene expression with aging and hypertension. We sought to examine the influence of adrenergic receptor stimulation on cardiac gene expression during hypertrophy using specific agonists and antagonists. Secondly, in an effort to approach mechanisms regulating expression of specific genes, we determined whether injection of DNA directly into the beating ventricle would be feasible in rats of advanced age. Male Wistar rats received either 2.4 mg/kg isoproterenol (ISO)/day, 9.9 mg/kg/day propranolol (PROP), both ISO and PROP, or vehicle (NaCl) via subcutaneously implanted osmotic pumps. In ISO rats, the ventricular weight/body weight ratio was increased by 27% after 1 day and peaked on day 3 (+40%). The levels of atrial natriuretic factor (ANF) and fibronectin (FN) mRNA in the left ventricles were elevated 20-fold and 13-fold in ISO rats, respectively, peaking at 3-days of infusion. Levels of transforming growth factor beta1 (TGFbeta1) mRNA were elevated 2-fold after 3 days of ISO infusion. The abundance of skeletal alpha-actin (SK) mRNA increased 4-fold after 1 day of ISO, and declined thereafter. ISO infusion decreased sarcoplasmic reticulum Ca2+ ATPase (SERCA) and preproenkephalin (PNK) gene expression by approximately 50% and induced a myosin heavy chain (MHC) isogene switch favoring beta-MHC. PROP partially inhibited the ISO-evoked increases in ANF and FN mRNA, completely prevented the ISO-induced changes in TGFbeta1 and SERCA mRNA, but had no effect on the ISO-stimulated changes in SK and PNK gene expression. Results of experiments using irreversible inhibitors of alpha-and beta-adrenergic receptors in conjunction with aortic constriction, indicated that these manipulations altered the levels but not the direction of gene expression and did not diminish the magnitude of hypertrophy. These results demonstrate that chronic ISO infusion elicits alterations in cardiac gene expression that are qualitatively identical to those observed in the hypertensive heart, but differ somewhat from those in senescent hearts. Luciferase activity and X-gal staining after injection of DNA into hearts of aging rodents demonstrated that this approach will be useful to determine mechanisms regulating transcription of genes in the heart during aging.
