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...
