Abstract
AimsTo investigate whether vascular endothelial growth factor B (VEGF-B) improves myocardial survival and cardiac stem cell (CSC) function in the ischemia–reperfusion (I/R) heart and promotes CSC mobilization and angiogenesis.Methods and resultsOne hour after myocardial ischemia and infarction, rats were treated with recombinant human VEGF-B protein following 24 h or 7 days of myocardial reperfusion. Twenty-four hours after myocardial I/R, VEGF-B increased pAkt and Bcl-2 levels, reduced p-p38MAPK, LC3-II/I, beclin-1, CK, CK-MB and cTnt levels, triggered cardiomyocyte protection against I/R-induced autophagy and apoptosis, and contributed to the decrease of infarction size and the improvement of heart function during I/R. Simultaneously, an in vitro hypoxia-reoxygenation (H/R)-induced H9c2 cardiomyocyte injury model was used to mimic I/R injury model in vivo; in this model, VEGF-B decreased LDH release, blocked H/R-induced apoptosis by inhibiting cell autophagy, and these special effects could be abolished by the autophagy inducer, rapamycin. Mechanistically, VEGF-B markedly activated the Akt signaling pathway while slightly inhibiting p38MAPK, leading to the blockade of cell autophagy and thus protecting cardiomyocyte from H/R-induced activation of the intrinsic apoptotic pathway. Seven days after I/R, VEGF-B induced the expression of SDF-1α and HGF, resulting in the massive mobilization and homing of c-Kit positive cells, triggering further angiogenesis and vasculogenesis in the infracted heart and contributing to the improvement of I/R heart function.ConclusionVEGF-B could contribute to a favorable short- and long-term prognosis for I/R via the dual manipulation of cardiomyocytes and CSCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0847-3) contains supplementary material, which is available to authorized users.
Highlights
Ischemic heart disease (IHD) is the leading cause of death in the modern world
vascular endothelial growth factor B (VEGF-B) could contribute to a favorable short- and long-term prognosis for I/R via the dual manipulation of cardiomyocytes and cardiac stem cell (CSC)
Rat hearts were subjected to ischemia by ligating the left anterior descending coronary artery (LAD) for 1 h, followed by reperfusion for 24 h to assess the effect of VEGF-B on myocardial infarct size and heart function in an I/R model in vivo
Summary
Ischemic heart disease (IHD) is the leading cause of death in the modern world. Myocardial infarction (MI) is usually initiated by myocardial ischemia resulting from theLi et al J Transl Med (2016) 14:116The VEGF family of archetypal angiogenic growth factors consists of five secreted dimeric glycoprotein growth factors in mammals: VEGF (or VEGF-A), VEGFB, VEGF-C, VEGF-D and PlGF (placenta growth factor) [2]. VEGF-mediated angiogenesis plays a critical role in the repair of ischemia/infarction, which is characterized by reduced blood supply to the heart [3, 4], until recently, VEGF-B was an exception to the family’s classical role in promoting angiogenesis [5, 6]. The absence of VEGF-B has been reported to lead to the decreased expression of fatty acid (FA) transport proteins in endothelial cells, which is associated with reduced lipid droplets in skeletal muscle and cardiomyocytes and improved insulin resistance in diabetes models [9,10,11]. The over-expression of VEGF-B improved cardiac contractility in rats after experimental MI [15]. It is unknown whether VEGF-B plays a role in short- and long-term prognosis following myocardial ischemia for the development of heart failure
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