Published online before print February 26, 2009, doi: 10.1161/CIRCRESAHA.108.172882
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© 2009 American Heart Association, Inc.
Integrative Physiology |
Gelsolin Regulates Cardiac Remodeling After Myocardial Infarction Through DNase I–Mediated Apoptosis
From the Toronto General Hospital (G.H.L., Y.S., Y.C., M.S., S.S., Y.M., S.A., F.D., M.C., G.D.C., Y.L., M.F., M.D.S., P.L.), University Health Network, Ontario; University of Toronto (S.Y.); Departments of Physiology and Pharmacology and Therapeutics Institute of Cardiovascular Sciences (L.A.K.), St Boniface General Hospital Research Centre, Winnipeg, Manitoba; and Canadian Institute of Health Research Group in Matrix Dynamics (C.A.M., P.L.), University of Toronto, Toronto, Ontario, Canada.
Correspondence to Peter P. Liu, MD, Scientific Director, Canada Institute of Health Research, NCSB11-1266, Toronto General Hospital, University Health Network, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada. E-mail peter.liu{at}utoronto.ca
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Abstract |
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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–/–) and wild-type littermates (GSN+/+) to left anterior descending coronary artery ligation or sham surgery. We found that GSN–/– mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN+/+ 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–/– 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–/– 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 • myocardial infarction • cardiac remodeling • apoptosis • deoxyribonuclease I
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Introduction |
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Gelsolin 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 Ca2+ 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 transient overexpression of the N-terminal half of gelsolin can induce apoptosis.6 Furthermore, gelsolin, which itself is a substrate of caspase-3, -7, and -9, is frequently downregulated in different human cancers that characteristically can escape apoptosis.12,13 These findings suggest that inhibition of the severing activity of gelsolin can preserve cell viability under stress conditions, while selectively activating gelsolin under proliferative conditions.
Full-length gelsolin can bind with actin and deoxyribonuclease (DNase) I, a key enzyme responsible for DNA degradation in apoptosis,14 in a noncompetitive manner to form a gelsolin/actin/DNase I ternary complex. This complex, when present intact, inhibits nuclear translocation and enzymatic activity of DNase I in vivo.15 In contrast, the N terminus of gelsolin, when present as a fragment, can disrupt the actin–DNase I interaction.16 The proapoptotic N-terminal gelsolin fragment actually competes with DNase I for binding to actin and, in turn, releases DNase I from actin to mediate apoptotic activity.
Cardiac gelsolin shares molecular and biochemical similarities to alveolar macrophage gelsolin and human serum gelsolin. The cardiac gelsolin is tightly bound to myofibrils and physiologically modulates the organization, assembly, and turnover of the thin filaments within the muscle cells.17 Recently, Yang et al have found increased gelsolin expression in failing human hearts.18 Whether the increased gelsolin plays a real contributory role during cardiac remodeling is unclear.
To clarify the potential role of gelsolin in cardiac remodeling after myocardial infarction (MI), we randomized gelsolin knockout mice (GSN–/–) and wild-type littermates (GSN+/+) for intervention involving either left anterior descending coronary artery ligation or sham surgery. The result demonstrated improved survival and cardiac function in GSN–/– mice. Gelsolin activity was elevated after MI and was associated with increased apoptosis. Interestingly, gelsolin appears to mediate apoptosis through DNase I activation in association with a gelsolin/HIF-1/DNase I complex, thus revealing a novel mechanism by which gelsolin modulates cardiac remodeling.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
Data Analysis
Images from immunoblotting, DNA laddering, and DNase zymography gel were evaluated by scanning and measuring the density of the bands using the software Quantity One. The data were expressed as means±SD unless otherwise indicated. The significance of comparison of mean values was determined by ANOVA or unpaired Student t test where appropriate, using a significance level of P<0.05.
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Results |
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Gelsolin Expression Was Elevated and Redistributed After MI
Through microarray gene expression analysis of 22 283 human genes, gelsolin was found to be markedly increased in human heart failure of both dilated and ischemic cardiomyopathy phenotypes (Figure I, A, in the online data supplement). To verify the microarray results and examine the role of gelsolin in postinfarction remodeling, left anterior descending coronary artery ligation was randomly performed in GSN–/– mice and wild-type littermates to create MI models (for the position of ligation, see supplemental Figure I, B). We confirmed the increased gelsolin protein after MI in mouse model by immunoblotting method. Notably, cleavage of gelsolin was only found in the ischemic border and infarcted zones of the GSN+/+ hearts (Figure 1A). Surprisingly, gelsolin expression was detected in significant amounts in the nuclear protein fraction of GSN+/+ hearts after MI 48 hours (Figure 1B), which suggested redistribution of gelsolin. Immunofluorescence analysis confirmed the dramatically increased expression and redistribution of gelsolin in ischemic border and infarcted zones of the GSN+/+ hearts (Figure 1C).
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Gelsolin can interact with phosphatidylinositol-3 kinase (PI3K) when it functions as an effector of the Ras-PI3K-Rac signaling cascade.4 We evaluated the protein levels of Ras and PI3K but found no statistically significant changes in these molecules between the 2 genotypes after MI (supplemental Figure I, C and D), suggesting that other mechanisms may regulate gelsolin after MI.
GSN–/– Mice Show Improved Survival and Cardiac Function After MI
After 4 weeks of left anterior descending coronary artery ligation, the survival was significantly higher in GSN–/– mice (67%, 18 of 27) compared with GSN+/+ mice (29%, 8 of 28, P<0.001; Figure 2A), whereas the sham-operated mice of either genotype all survived (100%, n=5 to 6 per group). Fifty-five to sixty percent of the deaths can be attributed to rupture, but the rupture rates were similar both genotypes (supplemental Figure II). The GSN–/– mice had similar infarct size at 48 hours after MI but showed smaller infarcts (17.0±4.0%) than GSN+/+ mice (35.2±5.6%, P<0.001) at 4 weeks by morphometric quantification (Figure 2B).
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Morphology showed that GSN–/– hearts exhibited significant attenuation of hypertrophy and dilatation (Figure 2B and 2C). Quantification of myocyte cross-sectional area in noninfarcted sites of GSN–/– mice confirmed much less hypertrophy (Figure 2C). Concordantly, heart weight/body weight and lung weight/body weight ratios were significantly smaller in GSN–/– mice (supplemental Table II). As estimated by picrosirius red staining for collagen, interstitial fibrosis was decreased in the ischemic border and infarcted areas in the GSN–/– hearts compared with the GSN+/+ hearts (Figure 2D). The expression levels of collagen I and III were higher in GSN+/+ hearts than GSN–/– hearts (Figure 2E). All of these data are consistent with a reduction of adverse cardiac remodeling and improved heart function and survival in the GSN–/– mice after MI.
To monitor heart function after MI, we performed echocardiography (Figure 3) and in vivo hemodynamic studies (supplemental Figure III and supplemental Table II). GSN–/– mice showed better preservation of ejection fraction and fractional shortening after MI (P<0.05). Compared with GSN+/+ mice, GSN–/– mice had smaller left ventricular (LV) end-diastolic and end-systolic dimension and LV end-systolic volume. Although the end-diastolic pressure is nonstatistically increased in GSN–/– mice, likely secondary to the actin stabilization through increased L-type calcium currents,19 the end-diastolic volume showed less increase than that of GSN+/+ mice. In summary, GSN–/– mice had improved survival and the surviving mice were protected against pathological LV remodeling after MI, with attenuated hypertrophy, less dilation, and improved cardiac function.
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MI Induced Less Apoptosis in GSN–/– Hearts
Using fluorescence labeling of DNA fragmentation with the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, we found that the number of TUNEL-positive cells, identified as cardiomyocytes by anti–cardiac myosin heavy chain staining (Figure 4A), was significantly decreased in the ischemic border zone of the GSN–/– mice compared with GSN+/+ mice (P<0.01; Figure 4B). Because apoptosis is characterized by internucleosomal cleavage of DNA into fragments of 180 to 200 bp as a result of endonuclease activity,20 whereas the TUNEL method can also label DNA repair in nonapoptotic myocytes21 and/or necrosis, we performed DNA laddering experiments. There was 7.8-fold less fragmentation in the ischemic border zones of GSN–/– mice compared with GSN+/+ mice (P<0.01; Figure 4C). DNA laddering was negligible in noninfarcted and infarcted areas and was not observed in sham-treated animals of both genotypes. Taken together, the data show that apoptosis occurred in ischemic border areas after MI but was significantly less in GSN–/– hearts, suggesting that gelsolin contributes to apoptosis after MI.
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MI Induced Gene Expression Changes in GSN–/– Mice
To investigate the potential mechanisms for protection against pathological LV remodeling after MI in GSN–/– mice, we noted from microarray analysis that the expression of genes related to stress response, pro- and antiapoptotic factors, and actin-binding proteins were affected as clusters. As shown in Figure 5, these changes were confirmed using quantitative real-time RT-PCR. After MI, there were significantly lower mRNA levels of DNase I, Bax, and serum response factor in the infarcted area and caspase-3, Fas-associating death domain containing protein, p53, tumor necrosis factor (TNF)-, heat shock protein (Hsp)70, and Hsp90 in the ischemic border area of GSN–/– mice compared with those of GSN+/+ mice, strongly suggesting a link between the presence of gelsolin and induction of apoptosis after MI. Strikingly, the most prominently changed gene was DNase I.
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DNase I Was Less Activated in GSN –/– Hearts After MI
To verify whether DNase I was activated after MI, proteins from cytoplasmic and nuclear extracts were immunoblotted using specific anti–DNase I antibody. Interestingly, there was less nuclear translocation of DNase I in GSN–/– mice after MI (P<0.01; Figure 6A). Immunostaining confirmed the nuclear translocation of DNase I and its involvement in apoptotic cells after MI (Figure 6B). We assessed the biological activity of DNase I in vitro using zymography. The cleared bands indicated local DNase digestion of DNA in the gels; mouse DNase 1 appeared as a band of 32 kDa. After MI, the biological activity of DNase I was significantly lower in the ischemic border area (P<0.01) and infarcted area (P<0.05) of GSN–/– hearts compared with that of GSN+/+ littermates (Figure 6C). Based on the knowledge that actin is the natural inhibitor of DNase I,15 we next examined the interaction of gelsolin/actin/DNase I in the actin complex. The gelsolin binding of actin, identified in the Pan-actin coprecipitation, was 3.2 times after MI compared with sham control in GSN+/+ hearts, and the DNasI/Pan-actin ratio was lower in the MI model of GSN–/– compared with that of GSN+/+ (1 and 2.71, respectively; supplemental Figure IV), meaning that cells with gelsolin are likely to produce more actin-barbed ends and more actin monomers, which bind DNaseI following the stimulus generated by the MI and try to attenuate its enhanced activation, particularly in terms of promoting cell death by apoptosis.
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HIF-1 Interacts With Gelsolin and DNase I
HIF-1 putatively binds to the promoter region of human DNase I.22 We examined the involvement of HIF-1 in our ischemia model and its potentially novel interactions with gelsolin. Interestingly, HIF-1 was strongly expressed in the ischemic and infarcted areas of GSN+/+ mice after MI (Figure 7A), to almost an identical degree and in the same spatial pattern as gelsolin and its cleaved forms (Figure 1A). These data raised the question of whether HIF-1 and gelsolin may associate. Accordingly, immunoprecipitation demonstrated that HIF-1 coprecipitated with gelsolin in GSN+/+ hearts after MI (Figure 7B). Moreover, we detected the colocalization of HIF-1 and gelsolin in GSN+/+ neonate myocytes after hypoxia by in vitro study (supplemental Figure V, B).
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Although HIF-1 sites appear to be necessary for the function of many if not most oxygen-regulated genes, a single HIF-1 site in isolation is not very active in inducing gene expression in response to hypoxia.23 We found that within a 1.5-kb region of the DNase I promoter, there are at least 3 binding sites for HIF-1 (–555, –607, and –1262 bp upstream of the start site). To examine the functional interactions of HIF-1 with the DNase I promoter, we prepared biotin-labeled DNase I oligonucleotide probes derived from the sequence of the DNase I promoter (for sequences, see the online data supplement). The wild-type probe contained 2 of HIF-1 binding sequences, whereas the mutant probe contained altered HIF-1 binding sequences. Electrophoretic mobility-shift assays (EMSAs) were performed. Two-hundred-fold excess unlabeled probe blocked binding with nuclear extracts, whereas the mutant probe did not bind or show competitive inhibition. A supershifted band was observed after addition of HIF-1 antibody in incubations with the wild-type probe but not with the mutant probe (Figure 7C). Luciferase assay showed that the relative luminescence is significantly increased after cotransfection of HIF-1 and PGL3-basic with DNase I promoter vectors in HL-1 cell line (Figure 7D).
Preserved Caspase Processing and Downregulation of Survival Factors in GSN–/– Mice
Of the 4 members of the caspase family we examined, caspase-3 and -8 showed significant change after MI, whereas caspase-6 and -7 cleavages could not be detected (data not shown). The full-length (32-kDa) products and cleavage fragments (10 to 12 kDa or 17 to 24 kDa)24 of caspase-3 were elevated in the infarcted zone of both genotypes compared with sham, whereas they were undetectable in sham-operated mice (Figure 8A). Interestingly, even though caspase-3 changes did not differ between GSN–/– and GSN+/+ mice, the caspase-3 changes did result in different cleavage products. These substrates included poly(ADP-ribose) polymerase (PARP), which is significantly less level of cleaved PARP in the infarcted area of GSN–/– mice (Figure 8B) and gelsolin, which was found cleaved only in the ischemic border and infarcted areas in GSN+/+ hearts after MI (Figure 1A). Another substrate is DNA fragmentation factor (DFF) 45/inhibitor of caspase-3–activated DNase (ICAD), which interacts with the DFF40/caspase-3-activated DNase (CAD) to form an inactive complex. Figure 8A showed also that the expression of full-length and cleaved ICADs were not significantly different between the gelsolin genotypes, suggesting that the difference in apoptosis between the 2 genotypes was not attributable to CAD release and translocation. Unlike the similarly expression of caspase-3 after MI in both genotypes, caspase-8 and its cleavage, as well as its downstream target, Bid, was less expressed in GSN–/– mice compared with GSN+/+ mice (Figure 8A). No cleaved Bid (tBid) was detected. Collectively, these data indicate that the difference of apoptosis observed between the gelsolin genotypes was at least partially mediated through pathways other than the caspases, such as DNase I.
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In addition, we examined survival signals that are typically involved in regulation of apoptosis. There was less suppression of phosphorylated Akt in GSN–/– mice after MI (Figure 8C). Moreover, the expression of Bcl-2 was significantly decreased in the ischemic border and infarcted areas of GSN+/+ mice, whereas its level was preserved in the GSN–/– mice (Figure 8D). These findings suggest the attenuation of apoptosis by activated Akt and Bcl-2 function may also take part in the regulation in the GSN–/– mice after MI.
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Discussion |
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This study demonstrated that gelsolin participates in broad pathological remodeling processes after MI. In the absence of gelsolin and following MI, hearts were protective, at least in part, through the regulation of apoptosis. Two important aspects contributed to this regulation. First, possibly in collaboration with HIF-1
, gelsolin appears to promote apoptosis in vivo through DNase I. Second, gelsolin contributes to the downregulation of survival factors to accelerate myocytes loss after MI through the caspase cleavage of PARP, reduction of Akt activation, and decrease of Bcl-2 expression. Numerous studies have demonstrated that apoptosis is induced by ischemic injuries in acute myocardial infarction25,26 and that myocyte death is attributable to apoptosis in failing hearts.27 Gelsolin regulates apoptosis.6,9 Like the other group,18 we detected enhanced expression of gelsolin in human heart failure, including dilated and ischemic cardiomyopathy. Furthermore, we demonstrate that this elevated gelsolin expression and redistribution occurred only in wild-type mice after MI. The improved cardiac remodeling and function in gelsolin knockout mice after MI are likely related to the reduced gelsolin-dependent apoptosis, associated with smaller infarcted area and less hypertrophy of individual myocytes in noninfarcted areas, all of which eventually lead to a reduced increase of cardiac mass, interstitial fibrosis, and amelioration of heart failure progression.
Gelsolin is cleaved by caspase-3 between residues Asp352 and Gly353.6 The N-terminal gelsolin fragment not only severs actin in a Ca2+-independent manner but also contributes to morphological alterations of apoptosis.6,7 A recent report showed that apoptosis induced by interferon- is mediated by the generation of the N-terminal half of gelsolin through caspase-3 activation.10 As shown in this study, gelsolin expression in GSN+/+ mice was increased and redistributed after MI. The increased caspase-3 after MI functioned only in the presence of gelsolin, as suggested by cleaved gelsolin occurring only in the ischemic border and infarcted areas of wild-type mice, which is consistent with the increased apoptosis in the wild-type mice. These data suggest that gelsolin contributes to MI-induced cardiomyocyte apoptosis. Interestingly, we have also observed that both activation of caspase-8 and full-length Bid but not truncated Bid were higher in wild-type mice than gelsolin-null mice after MI. Whether caspase-8 can also cleave gelsolin is not understood. However, an in vitro study using caspase-3–deficient MCF-7 cells demonstrated that only caspase-8 was activated by TNF- treatment accompanied by degradation of caspase substrates including gelsolin, PARP, and ICAD in apoptotic cells.28
The mechanism by which gelsolin stimulates apoptosis remains to be elucidated. Interestingly, the increased expression and cleavage of gelsolin after MI were contemporaneous with increased expression, nuclear translocation, and activation of DNase I in GSN+/+ mice. Gelsolin can increase the enzymatic activity of DNase I in vitro.29 Two possibilities may involve in the gelsolin-induced DNase I elevation. First, gelsolin may induce directly the expression of DNase I by transcriptional activation. Indeed, we observed that gelsolin translocated into nuclei after MI. A second possibility is that HIF-1 is the key activating partner because we found that HIF-1 associated with gelsolin (as shown by immunoprecipitation and colocalization in vitro study). Mouse DNase I have at least 3 hypoxia-response elements, which can bind to HIF-1. Similarly, within a 1500-bp sequence of the 5' upstream region of the human DNase I promoter, several hypoxia-response elements have been identified.22 Use of biotin-labeled probes encompassing 2 of the mouse HIF-1 binding sites in DNase I promoter sequence demonstrated the binding of HIF-1 in the DNase I promoter by EMSA in this study, and luciferase assay showed increased promoter activity when cotransfection of HIF-1 and DNase I promoter vectors in HL-1 cell line, highlighting the elevated DNase I level may be through the gelsolin/HIF-1/DNase I pathway.
In addition, our study showed the DNase I binding to actin was increased in wild-type compared to gelsolin-null mice. Because DNase I binds actin monomers and not as well to actin filaments,30 increased gelsolin activity may produce relatively more actin monomers and a higher ratio of DNase I bound to actin after MI in wild-type mice. The increased actin–DNase I complex may be even more susceptible to disruption by the N-terminal gelsolin and in turn cause the nuclear translocation of DNase I during apoptosis.
Cleavage of DNA during apoptosis is mediated by DNase 1,31 although a number of other enzymes including DNase X32 and DFF4033 may be involved. In this study, similar cleavage of ICADs in both gelsolin genotypes suggested that the observed difference of apoptosis was not caused by the release and translocation of DFF40 (CAD). Instead, the enhanced expression, nuclear translocation and degradative activity of DNase I may explain the increased apoptosis in the ischemic border area of the wild-type mice after MI.
The outcome of apoptosis is depended on a balance between apoptosis-promoting and apoptosis-inhibiting factors. PARP is involved in DNA repair to counteract cell death,34 whereas Akt and Bcl-2 are survival signals in cardiac tissues.35,36 The combined evidence of PARP cleavage coupled with reduced Akt activation or Bcl-2 expression in the wild-type mice suggests that gelsolin may also regulate these survival factors after MI.
In summary, after MI, gelsolin expression was increased and redistributed; cleaved gelsolin was also found in wild-type but not gelsolin-null ischemic hearts. These changes are associated with the higher mortality and pathological remodeling in wild-type mice. The adverse maladaption in wild-type mice may be caused by increased apoptosis, possibly a result of enhanced gelsolin-associated DNase I activation. Gelsolin-regulated apoptosis may be mediated through the gelsolin/HIF-1/DNase I pathway. Gelsolin may also in turn regulate survival factors such as phosphorylation of Akt and Bcl-2 expression. These findings provide a new potential target for inhibitory treatment after MI and heart failure.
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Acknowledgments |
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We thank Pam Arora for providing the murine gelsolin polyclonal antibody.
Sources of Funding
This work was supported by grants from the Canadian Institutes of Health Research, TACTICS fellowship, and the Heart and Stroke Foundation. P.L. is the Heart & Stroke/Polo Chair Professor of Medicine and Physiology, University of Toronto, and Scientific Director, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research.
Disclosures
None.
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Footnotes |
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Original received January 27, 2008; revision received January 17, 2009; accepted February 12, 2009.
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