Cardiac hypertrophy (CH) is a major risk factor of cardiovascular mortality and morbidity. In our studies attempts are made: 1. To identify genes, the expression of which is universally altered in cardiac hypertrophy, irrespective of the model. 2. To examine underlying mechanisms and functional significance of known biochemical changes in the heart, that are characteristic to specific models of CH. For this purpose, CH is induced in rats by different procedures, and morphological and biochemical characteristics of CH are examined. By means of subtractive hybridization, we cloned four genes that are overexpressed in different models of CH. In situ hybridization studies localized the expression of these genes to cells of connective tissue, and not to muscle cells. Thus, the expression of these genes is unlikely to be related to the hypertrophic process. An attempt was made to clone myocyte hypertrophy-specific genes. In addition, we described two different patterns of CH, best exemplified by the comparison of CH induced by isoproterenol (ISO) and by angiotensin II (AngII) and phenylephrine (PE): ISO induces CH in all rats. The extent of ISO-CH decreases with age, and is equal in males and females. In contrast, AngII induces CH that does not increase with age, and is greater in males than in females. Biochemically, AngII-CH and PE-CH are characterized by an increased ration of beta-myosin heavy chain (beta-MHC) to alpha-MHC, whereas ISO-CH presents with a decrease in this ratio. The change in MHC-isoforms by PE occurs equally in animals that respond to PE with CH, and in those that do not, indicating that the MHC change and CH are independent adaptive processes. Motility of labeled actin filaments on myosin extracted from hearts of PE-treated adult rats is normal, as determined by the 'in vitro motility assay' (performed by LMC, NHLBI). In contrast, actin motility on myosin extracted from hearts of ISO treated rats exhibit increased cycling rate. Thus, alpha0 and beta- adrenergic stimuli induce distinct patterns of CH, which differ in the susceptibility of populations to development of CH according to age and gender, and biochemical and functional changes that accompany CH. Changes in MHC composition in response to ISO and PE did not parallel changes in MHC-mRNA, indicating significant posttranscriptional modification in the expression of these genes. However, after cessation of the adrenergic stimuli, the ratio between MHC-isoforms returned to normal within days, in a process that involved mainly transcriptional control.
