Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3

Am J Physiol Heart Circ Physiol. 2014 Feb 15;306(4):H585-97. doi: 10.1152/ajpheart.00821.2013. Epub 2013 Dec 20.

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.

Keywords: Ang-1/Tie-2; VEGF/VEGFR2; angiogenesis; apelin; diabetic cardiomyopathy; sirtuin 3.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipokines
  • Angiopoietin-1 / genetics
  • Angiopoietin-1 / metabolism
  • Angiopoietin-2 / metabolism
  • Animals
  • Apelin
  • Apoptosis / physiology
  • Diabetic Cardiomyopathies / genetics
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / physiopathology
  • Diabetic Cardiomyopathies / therapy*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology
  • Heart / physiopathology
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Mice
  • Myocardium / metabolism*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / physiopathology
  • Neovascularization, Pathologic / therapy*
  • Reactive Oxygen Species / metabolism
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism
  • Receptors, Vascular Endothelial Growth Factor / genetics
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Sirtuin 3 / genetics*
  • Sirtuin 3 / metabolism
  • Up-Regulation / genetics*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Adipokines
  • Angiopoietin-1
  • Angiopoietin-2
  • Apelin
  • Apln protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • Receptor, TIE-2
  • Receptors, Vascular Endothelial Growth Factor
  • Sirtuin 3