Isoproterenol infusion induces alterations in expression of hypertrophy-associated genes in rat heart

Abstract

Chronic infusion of isoproterenol (Iso) in rats results in cardiac hypertrophy via incompletely understood mechanisms. Our purpose was to determine whether Iso infusion would alter the expression of genes associated with hypertrophy. Male Wistar rats received either 2.4 mg Iso.kg-1.day-1, 9.9 mg propranolol (Prop).kg-1.day-1, both Iso and Prop, or vehicle (NaCl) via subcutaneously implanted osmotic pumps. In Iso-treated rats, the ventricular weight-to-body weight ratio was increased by 27% after 1 day and peaked on day 3 (+ 40%). Levels of atrial natriuretic factor (ANF) and fibronectin (FN) mRNA in the left ventricles were elevated 20-fold and 13-fold in Iso-treated rats, respectively, peaking at 3 days of infusion. The increase in FN mRNA accumulation was at least partially accounted for by elevated expression of extra type IIIA and IIIB (EIIIA and EIIIB) splicing variants. Levels of transforming growth factor (TGF)-beta 1 mRNA were elevated twofold after 3 days of Iso infusion. The abundance of skeletal alpha-actin (SK) mRNA increased fourfold after 1 day of Iso and declined thereafter. Iso infusion decreased sarcoplasmic reticulum Ca(2+)-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 TGF-beta 1 and SERCA mRNA, but had no effect on the Iso-stimulated changes in SK and PNK gene expression. These results demonstrate that chronic Iso infusion elicits alterations in cardiac gene expression that are consistent with the development of myocyte hypertrophy and interstitial fibrosis and are directionally identical to those previously reported for pressure overload hypertrophy.