title: Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3.
abstract: Microvascular insufficiency contributes to cardiac hypertrophy and worsens heart dysfunction in diabetic cardiomyopathy. Our recent study shows that apelin may protect ischemic heart failure via upregulation of sirtuin 3 (Sirt3) and angiogenesis. This study investigated whether apelin promotes angiogenesis and ameliorates diabetic cardiomyopathy via activation of Sirt3. Wild-type (WT) and diabetic db/db mice were administrated with adenovirus-apelin to overexpressing apelin. In WT mice, overexpression of apelin increased Sirt3, VEGF/VEGFR2, and angiopoietin-1 (Ang-1)/Tie-2 expression in the heart. In vitro, treatment of endothelial cells (EC) with apelin increased VEGF and Ang-1 expression. In EC isolated from Sirt3KO mice, however, apelin treatment did not upregulate VEGF and Ang-1 expression. Moreover, apelin-induced angiogenesis was diminished in Sirt3KO mice. In db/db mice, the basal levels of apelin and Sirt3 expression were significantly reduced in the heart. This was accompanied by a significant reduction of capillary and arteriole densities in the heart. Overexpression of apelin increased Sirt3, VEGF/VEGFR2, and Ang-1/Tie-2 expression together with improved vascular density in db/db mice. Overexpression of apelin further improved cardiac function in db/db mice. Treatment with apelin significantly attenuated high glucose (HG)-induced reactive oxygen species (ROS) formation and EC apoptosis. The protection of apelin against HG-induced ROS formation and EC apoptosis was diminished in Sirt3KO-EC. We conclude that apelin gene therapy increases vascular density and alleviates diabetic cardiomyopathy by a mechanism involving activation of Sirt3 and upregulation of VEGF/VEGFR2 and Ang-1/Tie-2 expression.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Heng
authors.initials: H
authors.lastname: Zeng
authors.forename: Xiaochen
authors.initials: X
authors.lastname: He
authors.forename: Xuwei
authors.initials: X
authors.lastname: Hou
authors.forename: Lanfang
authors.initials: L
authors.lastname: Li
authors.forename: Jian-Xiong
authors.initials: JX
authors.lastname: Chen
mesh_terms: D054392:Adipokines; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D000073861:Apelin; D017209:Apoptosis / Q000502:physiology; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006321:Heart / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D054392:Adipokines; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000073861:Apelin; C402826:Apln protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D056566:Sirtuin 3
keywords: Ang-1/Tie-2; VEGF/VEGFR2; angiogenesis; apelin; diabetic cardiomyopathy; sirtuin 3