Inhibition of norepinephrine-induced cardiac hypertrophy in S100β transgenic mice

Abstract

We have recently reported that the Ca2+-binding protein S100β was induced in rat heart after infarction and forced expression of S100β in neonatal rat cardiac myocyte cultures inhibited α1-adrenergic induction of β myosin heavy chain (MHC) and skeletal α-actin (skACT). We now extend this work by showing that S100β is induced in hearts of human subjects after myocardial infarction. Furthermore, to determine whether overexpression of S100β 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, βMHC, and downregulation of αMHC. In transgenic mice, NE induced S100β transgene mRNA and protein, but provoked neither hypertrophy nor regulated cardiac-specific gene expression. NE induced hypertrophy in cultured CD1 but not S100β transgenic myocytes, confirming that the effects of S100β on cardiac mass reflected myocyte-specific responses. These transgenic studies complement in vitro data and support the hypothesis that S100β acts as an intrinsic negative regulator of the myocardial hypertrophic response.