Myocardial Injection of Apelin-Overexpressing Bone Marrow Cells Improves Cardiac Repair via Upregulation of Sirt3 after Myocardial Infarction

Abstract

Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ+/c-kit+/Sca1+ cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.

Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats’ hearts

“…This in turn improves myocardial hypertrophy and remodelling and results in maintaining myocardial tissue integrity. In line with this study, Li et al [28] reported that myocardial injection of apelin overexpressing bone marrow cells immediately after MI in mice decreased apoptosis. They also reported that treatment with apelin-13 (1 mg/kg/day) for three days before MI and for 14 days post-MI decreased myocardial apoptosis and hypertrophy [29].…”

Serum miR-335 Level is Associated with the Treatment Response to Trans-Arterial Chemoembolization and Prognosis in Patients with Hepatocellular Carcinoma

“…The result presented here shows decreased miR-335 expression levels in patients with HCC, which is consistent with a recent report indicating that miR-335 is reduced in HCC via aberrant promoter hypermethylation [35]. Besides, we found that HCC patients with low miR-335 levels depicted an unfavorable clinicopathologic features (high AFP values, vascular invasion, cirrhosis and large tumor volume), and those patients also had a poor response to TACE.…”

Hypoxia promotes bone marrow-derived mesenchymal stem cell proliferation through apelin/APJ/autophagy pathway

“…Autophagy has been reported to play a protective role in the heart following myocardial ischemia/reperfusion. In our previous study, we showed that treatment of post-MI mice with apelin-BMCs increased the expressions of autophagy gene LC3-II/I and Beclin-1 [21]. Some other researchers also reported that apelin/APJ might be related to the process of autophagy.…”