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.

Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

“…Apelin, expressed widely in various organs, including the heart, kidney, lung, brain, skeletal muscles, and gastrointestinal tract, is a multifunctional protein involved in angiogenesis, energy metabolism regulation, and fluid homeostasis [17,18]. Apelin is reported to have a beneficial effect in diabetes and its complications by promoting glucose uptake, improving insulin sensitivity, reducing body adiposity, enhancing brown adipogenesis, controlling diabetes-induced kidney hypertrophia and albuminuria, and suppressing oxidative stress [19][20][21][22]. A clinical study in CKD patients with cardiovascular disease indicated that patients with high serum apelin levels had higher adiponectin levels, greater eGFR, and lower IL-6, resistin, visfatin, and LDL-C levels, with a lower cardiovascular hospitalization and mortality [23].…”

The SIRT 3 Expression Profile is Associated with Pathological and Clinical Outcomes in Human Breast Cancer Patients

“…Sirtuin 3 (SIRT 3) is a member of Sirtuin family, the mammalian homologues of the silent information regulator 2 first discovered in Saccharomyces cerevisiae as an NAD+-dependent histone deacetylase [11,12]. The other Surtuin members, especially SIRT1 has been reported to be associated with the clinical features and prognosis of breast cancer.…”

Resistin-induced cardiomyocyte hypertrophy is inhibited by apelin through the inactivation of extracellular signal-regulated kinase signaling pathway in H9c2 embryonic rat cardiomyocytes

“…Apelin treatment abolishes development of cardiac hypertrophy, as well as preventing fibrosis progression and cardiac contractile dysfunction (37). In addition, apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3 (38). Previous studies demonstrated that apelin treatment contributes to cardioprotection in cardiac I/R injury, as well as angiotensin II-or isoproterenol-induced cardiac remodeling (39,40).…”