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Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis.
- Source :
-
Circulation research [Circ Res] 2009 Apr 10; Vol. 104 (7), pp. 896-904. Date of Electronic Publication: 2009 Feb 26. - Publication Year :
- 2009
-
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(-/-)) 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)-1alpha with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1alpha was similar to that of gelsolin, and HIF-1alpha was detected in the gelsolin complex by coprecipitation and HIF-1alpha 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-1alpha and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.
- Subjects :
- Actin Cytoskeleton metabolism
Animals
Caspases metabolism
Deoxyribonuclease I genetics
Disease Models, Animal
Disease Progression
Enzyme Activation
Fibrosis
Gelsolin deficiency
Gelsolin genetics
Gene Expression Regulation
Heart Failure genetics
Heart Failure pathology
Heart Failure physiopathology
Humans
Hypertrophy, Left Ventricular enzymology
Hypertrophy, Left Ventricular pathology
Hypertrophy, Left Ventricular physiopathology
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Myocardial Infarction genetics
Myocardial Infarction pathology
Myocardial Infarction physiopathology
Myocardium pathology
Promoter Regions, Genetic
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Signal Transduction
Time Factors
Up-Regulation
Ventricular Function, Left
Apoptosis
Deoxyribonuclease I metabolism
Gelsolin metabolism
Heart Failure enzymology
Myocardial Infarction enzymology
Myocardium enzymology
Ventricular Remodeling
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 104
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 19246681
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.108.172882