Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis.

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.

• Authors: Guo Hua Li, Yu Shi, Yu Chen, Mei Sun, Sawsan Sader, Yuichiro Maekawa, Sara Arab, Fayez Dawood, Manyin Chen, Geoffrey De Couto, Youan Liu, Masahiro Fukuoka, Stanley Yang, Ming Da Shi, Lorrie A Kirshenbaum, Christopher A McCulloch, Peter Liu
• Journal: Circulation research (Circ Res) Vol. 104 Issue 7 Pg. 896-904 (Apr 10 2009) ISSN: 1524-4571 [Electronic] United States
• PMID: 19246681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gelsolin
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-akt
• Deoxyribonuclease I
• Caspases

Topics

• Actin Cytoskeleton (metabolism)
• Animals
• Apoptosis
• Caspases (metabolism)
• Deoxyribonuclease I (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Enzyme Activation
• Fibrosis
• Gelsolin (deficiency, genetics, metabolism)
• Gene Expression Regulation
• Heart Failure (enzymology, genetics, pathology, physiopathology)
• Humans
• Hypertrophy, Left Ventricular (enzymology, pathology, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (enzymology, genetics, pathology, physiopathology)
• Myocardium (enzymology, 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
• Ventricular Remodeling