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
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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Circ. Res. 2009 104: 829-831.
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  R. Nishio and A. Matsumori Gelsolin and Cardiac Myocyte Apoptosis: A New Target in the Treatment of Postinfarction Remodeling Circ. Res., April 10, 2009; 104(7): 829 - 831. [Full Text] [PDF]
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