Gh Mediates α1-Adrenoreceptor-Induced Transactivation of Integrin Signaling and Hypertrophy in Cardiac Myocytes

Abstract

In cardiac myocytes, stimulation of the alpha(1)-adrenoreceptor(AR) leads to a hypertrophic phenotype. The Gh protein(transglutaminase II, TGII) is tissue type transglutaminase that transmits the alpha(1B)-AR signal with GTPase activity. Recent evidence suggests that integrin activation, in concert with G protein activation, might be essential for cardiomyocyte growth.In this study, our objectives were to evaluate how Gh and integrin interact to promote cardiomyocyte hypertrophy and to identify Gh molecular determinants and downstream signals involved. First, we observed the selectivity of alpha-adrenoceptors in norepinephrine(NE)-induced cardiac hypertrophy by protein synthesis and estimation of the constitutive genes MLC-2 and ß-MHC. NE-mediated hypertrophic responses activated ERK1,2 and their upstream regulators MEK1,2, which were inhibited by siRNA for Gh.We also identified significant activation of ß1-integrin in NE-induced cardiomyocyte hypertrophy. In addition, FAK and Shc, a regulator of FAK, were directly related with integrin and Gh protein in NE-induced cardiomyocyte hypertrophy. The activation of FAK and Shc were suppressed by siRNA for Gh. In conclusion, the hypertrophic response induced by norepinephrine in cardiomyocytes occurs through ß1-Integrin/Shc/FAK/MEK1,2/ERKs signal pathways via α1-AR/Gh.