ABSTRACT
Heart failure is the leading cause of death in diabetic patients. Recently we showed that apelin gene therapy attenuates heart failure following myocardial infarction. This study further explored the potential mechanisms by which apelin may reduce cardiac injury in Postmyocardial infarction (MI)) model of diabetes. Wild type and Sirt3 knockout (Sirt3 KO) mice were induced into diabetes by intra-peritoneal (i.p.) Streptozotocin (STZ). STZ mice were then subjected to MI followed by immediate intramyocardial injection with Adenovirus-apelin (Ad-apelin). Ad-apelin treatment resulted in over expression of apelin in the ischemic hearts of STZ mice. Apelin over expression led to a significant increase in Sirt3 expression. Apelin over expression significantly reduced gp91phox expression. This was accompanied by a significant reduction of reactive oxygen species formation. Ad-apelin treatment also dramatically reduced NF-κb-p65 expression in WT-STZ mice. Over expression of apelin further enhanced autophagy markers (LC3-II and beclin-1) expression in post-MI heart. Most intriguingly, knockout of Sirt3 in STZ mice abolished these beneficial effects of apelin treatment. In vitro, knockout of Sirt3 in EPCs significantly enhanced high glucose-induced ROS formation. Conversely, treatment of Sirt3 KO-EPCs with NADPH oxidase inhibitor led to two fold increase in LC3-II levels. Our studies demonstrate that apelin increases autophagy via up regulation of Sirt3 and suppression of ROS-NF-κb pathway in diabetic heart.
ABSTRACT
Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are the two ligands of the Tie-2 receptor, a receptor tyrosine kinase that is expressed on the endothelium. A balanced angiopoietin/Tie-2 system is critical for the maintenance of vascular integrity. We investigated the potential role of a disrupted angiopoietin/Tie-2 system on hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Using streptozotocin (STZ) mice subjected to myocardial ischemia, we examined the effects of shifting the Ang-2-to-Ang-1 ratio on myocardial infarction size, apoptosis, bone marrow (BM) cell-endothelial progenitor cell (EPC) differentiation, and angiogenesis. In control mice, myocardial ischemia increased expression of both Ang-2 and Tie-2. In STZ mice, Ang-2 expression was elevated, whereas Tie-2 expression was reduced, and neither was significantly altered by ischemia. Myocardial infarct size and apoptosis were increased in STZ compared with control mice. Using in vivo administration of an adenovirus containing Ang-1 or Ang-2, we found that shifting the Ang-2-to-Ang-1 ratio to favor Ang-1 reduced myocardial apoptosis and infarct size in STZ mice, while shifting the Ang-2-to-Ang-1 ratio to favor Ang-2 resulted in a significant increase in myocardial infarct size and apoptosis in control mice. Myocardial ischemia-stimulated BM cell-EPC differentiation was inhibited and myocardial angiogenesis was reduced in STZ mice. Systemic administration of Ad-Ang-1 restored BM cell-EPC differentiation and increased myocardial VEGF expression and angiogenesis in STZ mice. Our data demonstrate that disturbed angiopoietin/Tie-2 signaling contributes to the hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Restoration of the Ang-2-to-Ang-1 ratio may be a novel therapeutic strategy for the treatment of diabetic myocardial ischemic diseases.
