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.
Highlights
Sirtuins belong to a highly conserved family (Sirtuin 1–7) of histone/protein deacetylases and its activity is closely associated with the prolong lifespan of organisms such as yeast, worms and flies as well as mammalian [1]
bone marrow cell (BMC) treatment led to a significant increase in Sirt3 expression in post-myocardial infarction (MI) mice when compared with control post-MI mice (Fig 1A)
We examined whether BMC treatment increases vascular progenitor cells in the infarcted hearts
Summary
Sirtuins belong to a highly conserved family (Sirtuin 1–7) of histone/protein deacetylases and its activity is closely associated with the prolong lifespan of organisms such as yeast, worms and flies as well as mammalian [1]. Upregulation of Sirt expression improves their regenerative capacity in aged HSCs [21] Consistent with these findings, our recent study shows that loss of Sirt attenuates apelin-overexpressing BMC-mediated improvement of cardiac repair and function in post-MI [20]. Sirt in the stem cell therapy-mediated cardiac repair and functional recovery in post-MI remain undefined. We tested our hypothesis that Sirt in the BMCs is essential for the stem cell therapy-mediated angiogenesis and cardiac repair in post-MI. Using BMCs and EPCs from wild type (WT) mice and Sirt knockout (Sirt3KO) mice, this study was to determine: (1) whether loss of Sirt in EPCs reduces angiogenic growth factor expression and blunts their proangiogenic and anti-apoptotic capacities; (2) whether loss of Sirt in BMCs dampens BMC-mediated angiogenesis and cardiac repair in post-MI mice
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