The Endocrine Society’s 94th Annual Meeting and Expo, June 23–26, 2012 – Houston, TX

Abstract

Cardiac hypertrophy arises from poorly controlled hypertension and ischemic heart disease, progressing to dilation and cardiac failure as the leading cause of death in Americans.We have published that signaling from the membrane ERbeta receptor prevents cardiac hypertrophy and cardiac fibrosis, in-vitro and in-vivo. One important mechanism for development of the cardiac pathology involves Class I and Class II histone de-acetylases (HDAC) that promote or inhibit cardiac hypertrophy, respectively. We determined that Angiotensin II (AngII) and Endothelin-1 (ET-1), important factors that promote human cardiac hypertrophy, induced new protein synthesis of Class I HDAC2 in freshly isolated neonatal rat cardiomyocytes and stimulated HDAC2 gene transcription (qPCR). The pro-hypertrophic HDAC2 protein is activated by phosphorylation in the nucleus. AngII stimulated CK2 (creatine kinase) activity and its nuclear translocation where it phosphorylated HDAC2 at Ser392. All these effects of AngII/ET-1 were significantly blocked by 17-beta-estradiol (E2) or the ERbeta agonist DPN (each at 10nM). In contrast, AngII and ET-1 inhibited the synthesis of Class II HDACS 4 and 5 (anti-hypertrophic) in PKCdelta and protein kinase D (PKD)-linked fashion. E2 or DPN prevented AngII and ET-1-inhibited synthesis of these HDAC proteins, and the estrogenic compounds' effects were reversed by siRNA to ERbeta but not ERalpha siRNA. AngII also caused increased phosphorylation of Serine259/Serine498 in HDAC5 through PKCdelta activation, resulting in export of the anti-hypertrophic HDAC from nucleus into cytoplasm, thus contributing to hypertrophy. PKCdelta activation, Serine259 phosphorylation, and nuclear export of HDAC5 were all inhibited by E2 or DPN. HDAC4 phosphorylation at Ser632 is necessary for nuclear export and was stimulated by AngII in both a CAM kinase and PKD dependent fashion, inhibited by E2/DPN. Thus, AngII stimulated a linear pathway, involving CAM kinase II-PKCdelta-PKD, inhibited by E2 and DPN. AngII signaling to the decreased production and nuclear exclusion of anti-hypertrophic HDACs 4 and 5, but increased production and nuclear localization of the pro-hypertrophic HDAC2 in cardiomyocytes was suppressed by E2 and DPN. This reciprocal modulation of pro and anti-hypertrophic HDACs is a novel mechanism for prevention of cardiomyocyte hypertrophy in general, and contributes to the anti-hypertrophic functions of E2/ERbeta.