Loss of Sirt3 limits bone marrow cell-mediated angiogenesis and cardiac repair in post-myocardial infarction.

Abstract

Sirtuin-3 (Sirt3) has a critical role in the regulation of human aging and reactive oxygen species (ROS) formation. A recent study has identified Sirt3 as an essential regulator of stem cell aging. This study investigated whether Sirt3 is necessary for bone marrow cell (BMC)-mediated cardiac repair in post-myocardial infarction (MI). In vitro, BMC-derived endothelial progenitor cells (EPCs) from wild type (WT) and Sirt3KO mice were cultured. EPC angiogenesis, ROS formation and apoptosis were assessed. In vivo, WT and Sirt3 KO mice were subjected to MI and BMCs from WT and Sirt3 KO mice were injected into ischemic area immediately. The expression of VEGF and VEGFR2 was reduced in Sirt3KO-EPCs. Angiogenic capacities and colony formation were significantly impaired in Sirt3KO-EPCs compared to WT-EPCs. Loss of Sirt3 further enhanced ROS formation and apoptosis in EPCs. Overexpression of Sirt3 or treatment with NADPH oxidase inhibitor apocynin (Apo, 200 and 400 microM) rescued these abnormalities. In post-MI mice, BMC treatment increased number of Sca1+/c-kit+ cells; enhanced VEGF expression and angiogenesis whereas Sirt3KO-BMC treatment had little effects. BMC treatment also attenuated NADPH oxidase subunits p47phox and gp91phox expression, and significantly reduced ROS formation, apoptosis, fibrosis and hypertrophy in post-MI mice. Sirt3KO-BMC treatment did not display these beneficial effects. In contrast, Sirt3KO mice treated with BMCs from WT mice attenuated myocardial apoptosis, fibrosis and improved cardiac function. Our data demonstrate that Sirt3 is essential for BMC therapy; and loss of Sirt3 limits BMC-mediated angiogenesis and cardiac repair in post-MI.

• Authors: Heng Zeng, Lanfang Li, Jian-Xiong Chen
• Journal: PloS one (PLoS One) Vol. 9 Issue 9 Pg. e107011 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25192254 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Sirt3 protein, mouse
• Sirtuin 3

Topics

• Animals
• Apoptosis (genetics)
• Bone Marrow Cells (physiology)
• Bone Marrow Transplantation
• Cells, Cultured
• Fibrosis (genetics)
• Heart (physiology)
• Male
• Mice
• Mice, Knockout
• Myocardial Infarction (genetics, pathology, physiopathology)
• Myocardium (pathology)
• Neovascularization, Physiologic (genetics)
• Regeneration (genetics)
• Sirtuin 3 (genetics)