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.