MyD88 appears to be a key contributor to cardiac inflammation, mediating cytokine production and T-helper-1/2 cytokine balance, increasing coxsackie-adenoviral receptor and p56(lck) expression and viral titers after CVB3 exposure. Absence of MyD88 confers host protection possibly through novel direct activation of IRF-3 and IFN-beta.

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Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase-dependent (p300-HAT-dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PEinduced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT-dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-κB, and TGF-β-Smad signaling pathways.

Abstract-Gelsolin, a calcium-regulated actin severing and capping protein, is highly expressed in murine and human hearts after myocardial infarction and is associated with progression of heart failure in humans. The biological role of gelsolin in cardiac remodeling and heart failure progression after injury is not defined. To elucidate the contribution of gelsolin in these processes, we randomly allocated gelsolin knockout mice (GSN Ϫ/Ϫ ) and wild-type littermates (GSN ϩ/ϩ ) to left anterior descending coronary artery ligation or sham surgery. We found that GSN Ϫ/Ϫ mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN ϩ/ϩ mice. Gene expression and protein analysis identified significantly lower levels of deoxyribonuclease (DNase) I and reduced nuclear translocation and biological activity of DNase I in GSN Ϫ/Ϫ mice. Absence of gelsolin markedly reduced DNase I-induced apoptosis. The association of hypoxia-inducible factor (HIF)-1␣ with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1␣ was similar to that of gelsolin, and HIF-1␣ was detected in the gelsolin complex by coprecipitation and HIF-1␣ bound to the promoter of DNase I in both gel-shift and promoter activity assays. Furthermore, the phosphorylation of Akt at Ser473 and expression of Bcl-2 were significantly increased in GSN Ϫ/Ϫ mice, suggesting that gelsolin downregulates prosurvival factors. Our investigation concludes that gelsolin is an important contributor to heart failure progression through novel mechanisms of HIF-1␣ and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy. Key Words: gelsolin Ⅲ myocardial infarction Ⅲ cardiac remodeling Ⅲ apoptosis Ⅲ deoxyribonuclease I G elsolin is a widely distributed actin-binding protein consisting of six domains (G1 to -6) with a salt bridge between G2 and G6 (latch helix) when it is inactive. Gelsolin mediates multiple cellular functions including cell motility, morphogenesis, and actin cytoskeletal remodeling. 1,2 The most extensively examined roles of gelsolin are its actin filament severing, capping, uncapping, and nucleating activities. The severing activity of gelsolin is regulated by Ca 2ϩ and pH, whereas polyphosphoinositides (particularly PIP2) regulate uncapping. 2,3 In addition to its remodeling of actin filaments, gelsolin can also regulate signal transduction through the integrin and small GTPase (Ras-Rac)-mediated pathways. 4,5 There are conflicting data on the pro-and antiapoptotic functions of gelsolin. 6 -10 On the one hand, full-length gelsolin, its C-terminal half, and its phosphatidylinositol 4,5-bisphosphate complexes are mostly antiapoptotic. 8,11 In contrast, the N-terminal half of gelsolin is potentially proapoptotic because gelsolin-deficient cells show retarded onset of apoptosis and tra...