Background: Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms. Methods: C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively. C57Bl/6J mice 20 months old were used to study age-induced cardiac fibrosis. Liraglutide treatment of 30 µg/kg/day-300 µg/kg s.c. twice daily was administered for 4 weeks. Results: Liraglutide treatment attenuated obesity, hypertension and age-induced increases in interstitial cardiac fibrosis and expression of inflammatory and oxidative stress markers. Conclusions: These observations identify a potential role for liraglutide in the prevention of cardiac fibrosis and identify molecular mechanisms associated with these effects.

Glucagon-like peptide-1 (GLP-1) based therapies are used to treat type II diabetes via increasing insulin secretion and inhibiting glucagon production. Recent evidence suggests that activating the GLP-1 receptor may also mediate direct vaso-protective effects. Therefore the objective of the study was to determine whether GLP-1R stimulation conferred cardio- and vaso-protection in a non-diabetic setting using the angiotensin (Ang) II infusion model of hypertension and cardiovascular dysfunction. Male C57Bl/6J mice (4-6 months) were assigned to one of the following 4 week treatment protocols: 1) vehicle (saline), 2) Ang II (800ng/kg/day), 3) Ang II + liraglutide (30μg/kg/day), 4) Ang II + liraglutide (300μg/kg/day). All treatments were administered via osmotic mini-pumps (s.c). After 4 weeks the effect of liraglutide treatment on blood pressure, vascular function and cardiac remodelling was examined. Liraglutide (both doses) attenuated Ang II-induced increase in systolic blood pressure (Ang II: 175.3 ± 8.6mmHg vs Ang II+Lirag (30) 150.2 ± 6.4 mmHg or Ang II+Lirag (300): 145.4 ± 6.9 mmHg) without affecting blood glucose levels. Liraglutide (both doses) completely prevented Ang II-induced endothelial dysfunction (% maximum relaxation: Ang II=50.7 ± 7.8%; Ang II+Lirag (30)=82.7 ± 5.8; Ang II+Lirag (300)=81.5 ± 6.1%). In the heart, liraglutide prevented Ang II-induced cardiomyocyte hypertrophy (n=7-10; p<0.05) and reduced collagen deposition (% collagen expression: Ang II=4.4 ± 0.5 vs Ang II+Lirag(300)=2.9 ± 0.3; n=7-9; p<0.01). This anti-fibrotic effect was attributed to reduced fibroblast/myofibroblast expression as well as decreased inflammation with reduced NFκB and MCP-1 expression and decreased oxidative stress with a significant reduction in superoxide production using high dose of liraglutide. Overall, stimulation of GLP-1R in a non-diabetic setting protected against Ang II-mediated cardiac hypertrophy, cardiac fibrosis and vascular dysfunction, indicating potential for use of GLP-1 based therapies in treatment of cardiovascular disease independent of diabetes.