Gelsolin, a Ca(2+) -regulated actin filament severing, capping, and nucleating protein, is an ubiquitous, multifunctional regulator of cell structure and metabolism. More recent data show that gelsolin can act as a transcriptional cofactor in signal transduction and its own expression and function can be influenced by epigenetic changes. Here, we review the functions of the plasma and cytoplasmic forms of gelsolin, and their manifold impacts on cancer, apoptosis, infection and inflammation, cardiac injury, pulmonary diseases, and aging. An improved understanding of the functions and regulatory mechanisms of gelsolin may lead to new considerations of this protein as a potential biomarker and/or therapeutic target.

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...

Background— The innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor-associated kinase-4 (IRAK-4), downstream of Toll/interleukin-1 receptor signaling, has an essential role in regulating the innate immune response. The present study was designed to determine the mechanism by which IRAK-4 is responsible for the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI. Methods and Results— Experimental MI was created in IRAK-4 −/− and wild-type mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks after MI. IRAK-4 −/− mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less proinflammatory and Th1 cytokine expression mediated by suppression of nuclear factor-κB and c-Jun N-terminal kinase activation. IRAK-4 −/− mice had fewer infiltrations of CD45 + leukocytes and CD11c + dendritic cells, inhibition of apoptosis, and reduced fibrosis and nitric oxide production. Cardiac dendritic cells in IRAK-4 −/− mice were relatively immature or functionally naïve after MI in that they demonstrated less cytokine and costimulatory molecule gene expression. Furthermore, IRAK-4 −/− dendritic cells have less mobilization capacity. Transfer of wild type-derived bone marrow dendritic cells into IRAK-4 −/− mice for functional dendritic cell reconstitution negated the survival advantage and reduced the cardiac dilation observed with IRAK-4 −/− mice at 28 days after MI. Conclusions— Deletion of IRAK-4 has favorable effects on survival and left ventricular remodeling after MI through modification of the host inflammatory process by blunting the detrimental bone marrow dendritic cells mobilization after myocardial ischemia.

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Neutrophil gelatinase-associated lipocalin, or NGAL, an acute phase protein, is part of the lipocalin family. NGAL is highly induced in inflammatory conditions and ischemia, and is a critical component of innate immunity to bacterial infection. Recently, NGAL has been proven as an emerging biomarker for predicting acute kidney injury (AKI). Meanwhile, numerous studies have also demonstrated that NGAL may be a potential biomarker for the diagnosis, prediction, prevention, and prognosis of non--AKI diseases such as chronic kidney diseases, vascular disorders, cancer, preeclampsia, and allergies. This article systematically reviews the clinical utilities of NGAL as a new biomarker for non--AKI diseases.

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and when excessive can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain-containing protein 1(Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone. Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1 -/- , RIP2 -/- or wild-type (WT) mice to transverse aortic constriction (TAC) or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: Nod1 and RIP2 proteins were up-regulated in the heart after TAC, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 -/- and RIP2 -/- mice subjected to TAC exhibited better survival, improved cardiac function and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis including NF-κB and MAPK-GATA4/p300, were reduced in both Nod1 -/- and RIP2 -/- mice after TAC compared with WT mice. Co-immunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/ RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF-κB signalling and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions. Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling following stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response and mitochondrial energy metabolism in stressed cardiomyocytes. Thus Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

Background-Regression of left ventricular mass with nocturnal hemodialysis has been observed.

ZnO films are prepared on glass substrates by pulsed laser deposition (PLD) at different oxygen pressures, and the effects of oxygen pressure on the structure and optoelectrical properties of as-grown ZnO films are investigated. The results show that the crystallite size and surface roughness of the films increase, but the carrier concentration and optical energy gap E g decrease with increasing oxygen pressure. Only UV emission is found in the photoluminescence (PL) spectra of all the samples, and its intensity increases with oxygen pressure. Furthermore, there are marked differences in structure and properties between the films grown at low oxygen pressures (0.003 and 0.2 Pa) and the films grown at high oxygen pressures (24 and 150 Pa), which is confirmed by the fact that the crystallite size and UV emission intensity markedly increase, but the carrier concentration markedly decreases as oxygen pressure increases from 0.2 to 24 Pa. These results show that the crystal quality, including the microstructural quality and stoichiometry proportion, of the prepared ZnO films improves as oxygen pressure increases, particularly from 0.2 to 24 Pa.