Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.25.1 (
deoxyribonuclease
)
1,471
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis. 1935 5
