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Inhibition of histone deacetylases (HDACs) by valproic acid (VPA) attenuates inflammatory, hypertrophic, and fibrotic responses in the hearts of spontaneously hypertensive rats (SHRs); however, the molecular mechanism is still unclear. We hypothesized that HDAC inhibition (HDACi) attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor (MR) in SHRs. Seven-week-old SHRs and Wistar-Kyoto rats were treated with an HDAC class I inhibitor (0.71% w/v in drinking water; VPA) for 11 weeks. Sections of heart were visualized after trichrome stain as well as H&E stain. Histone modifications, such as acetylation (H3Ac [acetylated histone 3]) and fourth lysine trimethylation (H3K4me3) of histone 3, and recruitment of MR and RNA polymerase II (Pol II) into promoters of target genes were measured by quantitative real-time polymerase chain reaction after chromatin immunoprecipitation assay. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation with anti-MR antibody. Treatment with VPA attenuated cardiac hypertrophy and fibrosis. Although treatment with VPA increased H3Ac and H3K4me3 on promoter regions of MR target genes, expression of MR target genes as well as recruitment of MR and Pol II on promoters of target genes were decreased. Although HDACi did not affect MR expression, it increased MR acetylation. These results indicate that HDACi attenuates cardiac hypertrophy and fibrosis through acetylation of MR in spontaneously hypertensive rats.

INTRODUCTIONGender differences in the development of cardiovascular diseases have been documented in both human and animal studies. The rate of incidence of cardiovascular disease is lower in premenopausal women than in men, but increases sharply in postmenopausal women (1). Among the clinical consequences of postmenopausal estrogen deficiency, the deaths associated with cardiovascular diseases represent the largest concern in public health. Many studies have demonstrated that estrogen replacement therapy reduces the risk of cardiovascular disease in postmenopausal women (2). Animal studies also demonstrate gender differences in the development of cardiovascular diseases (3-5). Thus, circulating endogenous estrogen is proposed to protect against cardiovascular disease. However, mechanisms by which estrogen induces its protective effects are not fully understood.Various vasoactive substances and growth factors have been implicated in cardiac and vascular remodeling, as well as further degenerative transformation of these tissues (6). A critical role of the cardiac renin-angiotensin system (RAS), among others, has been recognized (7,8). Increased activity of the cardiac RAS has been confirmed both in humans (9) and animal models of cardiac failure (10, 11), whereas inhibition of the RAS decreased ventricular remodeling and improved cardiac function (12, 13).Cardiac hypertrophy is known to be one of the most critical risk factors of heart diseases. It has been demonstrated that monocrotaline (MCT) treatment produces pulmonary hypertension and right ventricular (RV) hypertrophy in male rats but not in female rats (4, 14). We previously found enhanced gene expressions of the cardiac RAS in the hypertrophied RV of male rats (15). The present study evaluated 1) the importance of the ovairan function and the RAS in the progression of the pulmonary hypertension, and 2) RV hypertrophy in MCT treated rats. We examined the cardiac expression of genes that contribute to the pathogenesis of cardiac hypertrophy, such as the RAS components, TGF-1, and endothelin-1 as well as histological changes in the lung and heart. Although this MCT rat model has no human equivalent, as a study design, we used a system of MCT-induced cardiopulmonary dysfunction to investigate possible beneficial effects of estrogen and inhibition of angiotensin converting enzyme. J Korean Med Sci 2003; 18: 641-8 ISSN 1011-8934 Copyright � The Korean Academy of Medical Sciences 641 Estrogen and Enalapril attenuate the Development of Right Ventricular Hypertrophy induced by Monocrotaline in Ovariectomized RatsThe present study evaluated the importance of ovarian functions and the reninangiotensin system in the progression of the right ventricular (RV) hypertrophy. Female Sprague-Dawley rats were bilaterally ovariectomized (Ovx) and injected with monocrotaline (MCT, 60 mg/kg, sc). Four weeks after MCT-treatment, only the male and Ovx female rats showed marked RV hypertrophy. The hypertrophied RV of the male-MCT and Ovx-MCT rats exhibited remarkably elevate...

Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats.