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

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

Research output: Contribution to journalArticle

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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)-1α with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1α was similar to that of gelsolin, and HIF-1α was detected in the gelsolin complex by coprecipitation and HIF-1α 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-1α and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.

Original languageEnglish
Pages (from-to)896-904
Number of pages9
JournalCirculation Research
Volume104
Issue number7
DOIs
Publication statusPublished - 2009 Apr 10
Externally publishedYes

Fingerprint

Gelsolin
Deoxyribonuclease I
Myocardial Infarction
Apoptosis
Hypoxia-Inducible Factor 1
Heart Failure
Actin Capping Proteins
Down-Regulation
Deoxyribonucleases
Actin Cytoskeleton
Knockout Mice
Hypertrophy
Ligation

Keywords

  • Apoptosis
  • Cardiac remodeling
  • Deoxyribonuclease I
  • Gelsolin
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis. / Li, Guo Hua; Shi, Yu; Chen, Yu; Sun, Mei; Sader, Sawsan; Maekawa, Yuichiro; Arab, Sara; Dawood, Fayez; Chen, Manyin; De Couto, Geoffrey; Liu, Youan; Fukuoka, Masahiro; Yang, Stanley; Da Shi, Ming; Kirshenbaum, Lorrie A.; McCulloch, Christopher A.; Liu, Peter.

In: Circulation Research, Vol. 104, No. 7, 10.04.2009, p. 896-904.

Research output: Contribution to journalArticle

Li, GH, Shi, Y, Chen, Y, Sun, M, Sader, S, Maekawa, Y, Arab, S, Dawood, F, Chen, M, De Couto, G, Liu, Y, Fukuoka, M, Yang, S, Da Shi, M, Kirshenbaum, LA, McCulloch, CA & Liu, P 2009, 'Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis', Circulation Research, vol. 104, no. 7, pp. 896-904. https://doi.org/10.1161/CIRCRESAHA.108.172882
Li, Guo Hua ; Shi, Yu ; Chen, Yu ; Sun, Mei ; Sader, Sawsan ; Maekawa, Yuichiro ; Arab, Sara ; Dawood, Fayez ; Chen, Manyin ; De Couto, Geoffrey ; Liu, Youan ; Fukuoka, Masahiro ; Yang, Stanley ; Da Shi, Ming ; Kirshenbaum, Lorrie A. ; McCulloch, Christopher A. ; Liu, Peter. / Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis. In: Circulation Research. 2009 ; Vol. 104, No. 7. pp. 896-904.
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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)-1α with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1α was similar to that of gelsolin, and HIF-1α was detected in the gelsolin complex by coprecipitation and HIF-1α 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-1α and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.",
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AU - Shi, Yu

AU - Chen, Yu

AU - Sun, Mei

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AU - Maekawa, Yuichiro

AU - Arab, Sara

AU - Dawood, Fayez

AU - Chen, Manyin

AU - De Couto, Geoffrey

AU - Liu, Youan

AU - Fukuoka, Masahiro

AU - Yang, Stanley

AU - Da Shi, Ming

AU - Kirshenbaum, Lorrie A.

AU - McCulloch, Christopher A.

AU - Liu, Peter

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KW - Deoxyribonuclease I

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KW - Myocardial infarction

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