Abstract 955: Apelin Reverses Pathologic Ventricular Remodeling in the db/db Obese Mouse
Background Heart failure frequently complicates diabetes, though the mechanistic basis for this remains unknown. The novel peptide apelin has recently been shown to have significant inotropic and angiogenic properties. To determine the role of apelin in diabetic cardiomyopathy, we assessed cardiac apelin expression in leptin receptor-deficient db/db mice. In addition, we evaluated the effect of chronic apelin infusion on cardiac remodeling in these mice.
Methods db/db and db/+ control mice underwent cardiac magnetic resonance (CMR) imaging at 5, 9, 13, and 17 weeks of age (n = 6 all groups). Left ventricular end-diastolic volume (LVEDV) and ejection fraction (EF) were determined. For apelin infusion, osmotic pumps containing apelin (2 mg/kg/d) or saline were implanted subcutaneously in db/db and db/+ mice aged 9 weeks (n = 4 all groups). After 4 weeks of infusion, CMR was performed and the mice sacrificed. Real time quantitative RT-PCR was performed to measure cardiac expression of αMHC and apelin.
Results Compared to control, db/db mice developed progressive ventricular remodeling, with an increase in LVEDV (57 vs. 49 mL at 17 weeks; p = 0.01) and a decrease in LVEF (70.2 vs. 68.1% at 17 weeks; p < 0.01). αMHC expression was decreased at 10 (3.6-fold; p < 0.01) and 15 (1.5-fold; p = 0.04) weeks relative to control, consistent with ongoing pathologic remodeling. Notably, relative to control, apelin was upregulated 2.5-fold at 10 weeks (p < 0.01), but downregulated 3.1-fold at 15 weeks (p = 0.03) (n = 5 all groups). To determine whether restoration of apelin could modify the remodeling process, we continuously infused apelin or saline in 9 week db/db and db/+ mice for 4 weeks. In both db/db and db/+ mice, EF was significantly increased after 4 weeks. In db/+ mice, there were no significant differences in LVEDV at 4 weeks (49 vs. 47 mL for saline and apelin). However, in db/db mice, LVEDV was decreased (54 vs. 46 mL; p < 0.01). Moreover, apelin infusion reversed the decrease in αMHC expression seen in db/db mice. There were no differences in body weight between saline- and apelin-treated mice at baseline and 4 weeks.
Conclusion db/db mice develop structural, functional, and molecular changes consistent with heart failure. These changes are ameliorated by chronic apelin treatment.