Inhibition of Norepinephrine-induced Cardiac Hypertrophy in S100[small beta, Greek] Transgenic Mice

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Abstract

We have recently reported that the Ca2+-binding protein S100[small beta, Greek] was induced in rat heart after infarction and forced expression of S100[small beta, Greek] in neonatal rat cardiac myocyte cultures inhibited [small alpha, Greek] (1-adrenergic) induction of [small beta, Greek] myosin heavy chain (MHC) and skeletal [small alpha, Greek]-actin (skACT). We now extend this work by showing that S100[small beta, Greek] is induced in hearts of human subjects after myocardial infarction. Furthermore, to determine whether overexpression of S100[small beta, Greek] was sufficient to inhibit in vivo hypertrophy, transgenic mice containing multiple copies of the human gene under the control of its own promoter, and CD1 control mice were treated with norepinephrine (NE) (1.5 mg/kg) or vehicle, intraperitoneally twice daily for 15 d. In CD1, NE produced an increase in left ventricular/body weight ratio, ventricular wall thickness, induction of skACT, atrial natriuretic factor, [small beta, Greek]MHC, and downregulation of [small alpha, Greek]MHC. In transgenic mice, NE induced S100[small beta, Greek] transgene mRNA and protein, but provoked neither hypertrophy nor regulated cardiac-specific gene expression. NE induced hypertrophy in cultured CD1 but not S100[small beta, Greek] transgenic myocytes, confirming that the effects of S100[small beta, Greek] on cardiac mass reflected myocyte-specific responses. These transgenic studies complement in vitro data and support the hypothesis that S100[small beta, Greek] acts as an intrinsic negative regulator of the myocardial hypertrophic response. (J. Clin. Invest. 1998. 102:1609-1616.)

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