INHIBITION OF NOREPINEPHRINE-INDUCED CARDIAC-HYPERTROPHY IN S100-BETATRANSGENIC MICE

We have recently reported that the Ca2+-binding protein S100 beta was induced in rat heart after infarction and forced expression of S100 be ta in neonatal rat cardiac myocyte cultures inhibited alpha(1)-adrener gic induction of beta myosin heavy chain (MHC) and skeletal alpha-acti n (skACT). We now extend this work by showing that S100 beta is induce d in hearts of human subjects after myocardial infarction. Furthermore , to determine whether overexpression of S100 beta was sufficient to i nhibit in vivo hypertrophy, transgenic mice containing multiple copies of the human gene under the control of its own promoter, and CD1 cont rol mice were treated with norepinephrine (NE) (1.5 mg/kg) or vehicle, intraperitoneally twice daily for 15 d. In CD1, NE produced an increa se in left ventricular/body weight ratio, ventricular wall thickness, induction of skACT, atrial natriuretic factor, beta MHC, and downregul ation of alpha MHC. In transgenic mice, NE induced S100 beta transgene mRNA and protein, but provoked neither hypertrophy nor regulated card iac-specific gene expression. NE induced hypertrophy in cultured CD1 b ut not S100 beta transgenic myocytes, confirming that the effects of S 100 beta on cardiac mass reflected myocyte-specific responses. These t ransgenic studies complement in vitro data and support the hypothesis that S100 beta acts as an intrinsic negative regulator of the myocardi al hypertrophic response.