Abstract 9663: Sirt7 Contributes to Proper Wound Healing After Murine Model of Myocardial Infarction by Modulating the Fibroblast Differentiation
Introduction: Sirt7 is the only mammalian sirtuin which is localized predominantly in the nucleoli. To date, little is known about the role of Sirt7 in wound healing in the setting of acute cardiac insult.
Hypothesis: Sirt7 contributes to proper wound healing processes after myocardial infarction (MI) by modulating cardiac fibroblast function.
Methods: MI was created in 10-week-old male homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery. Cardiac function and structure were assessed by micromanometer catheter, echocardiography, histology and gene expression analyses. Sirt7 knockdown experiments were performed with rat neonatal cardiac fibroblast and human skin fibroblast.
Results: Sirt7 transcript expression was increased by 2.5-fold in the border zone (BZ) of myocardial tissues at 3 days after MI in WT mice. Body weight, heart rate, systolic blood pressure, echocardiographic and hemodynamic parameters did not differ between Sirt7-/- and WT mice at 3 days after MI. However, the number of mice that died of cardiac rupture within 1 weeks after MI was significantly higher in Sirt7-/- mice (63%, 12 of 19 mice) than in WT mice (21%, 5 of 24 mice) (P<0.01). Histological analysis revealed that interstitial fibrosis and α-SMA positive fibroblast in the BZ of myocardium was significantly decreased in Sirt7-/- mice, despite the same infarct size between both groups. These changes were accompanied by the reduction in collagen I and α-SMA gene expression. In vitro, Sirt7 transcripts expression was readily detectable in total RNA isolated from rat neonatal cardiac fibroblast and human skin fibroblast. Knockdown of endogenous Sirt7 expression by small interfering RNA attenuated TGF-β1-induced PAI-1 and α-SMA expression. Conversely, adenovirus-mediated overexpression of Sirt7 augmented TGF-β1-induced α-SMA gene expression. TGF-β1-induced ERK phosphorylation was blocked by Sirt7 knockdown. However, phosphorylation and translocation of smad2 was not changed by Sirt7 knockdown.
Conclusions: Sirt7 modulates cardiac fibroblast differentiation which is dependent on ERK signaling. Sirt7 contributes to proper wound healing process after experimental myocardial infarction.
- © 2011 by American Heart Association, Inc.