Liraglutide protects cardiac function in diabetic rats through the PPARα pathway

Abstract

Increasing evidence shows that diabetes causes cardiac dysfunction. We hypothesized that a glucagon-like peptide-1 analogue, liraglutide, would attenuate cardiac dysfunction in diabetic rats. Twenty-four Sprague Dawley (SD) rats were divided into 2 groups fed either a normal diet (normal, n = 6) or a high-fat diet (HFD, n = 18) for 4 weeks. Then, the HFD rats were injected with streptozotocin (STZ) to create a diabetic rat model. Diabetic rats were divided into 3 subgroups receiving vehicle (diabetic, n = 6), a low dose of liraglutide (Llirag, 0.2 mg/kg/day, n = 6) or a high dose of liraglutide (Hlirag, 0.4 mg/kg/day, n = 6). Metabolic parameters, systolic blood pressure, heart rate, left ventricular (LV) function, and whole genome expression of the heart were determined. Diabetic rats developed insulin resistance, increased blood lipid levels and oxidative stress, and impaired LV function, serum adiponectin, NO. Liraglutide improved insulin resistance, serum adiponectin, NO, heart rate and LV function and reduced blood triglyceride, total cholesterol levels and oxidative stress. Moreover, liraglutide increased heart Nr1h3 , Ppar-α and Srebp expression and reduced Dgat , and Angptl3 expression. Liraglutide prevented in cardiac dysfunction by activating the PPARα pathway to inhibit Dgat expression and oxidative stress in diabetic rats.

Keywords: Diabetes; PPAR; cardiac function; glucagon-like peptide-1 analogue.

Figure 1. Effect of liraglutide on metabolic indexes in diabetic rats.

(A) Body weight, (B) fasting blood glucose, (C) blood glucose in OGTT, (D) AUC in OGTT, (E) TC, (F) TG, (G) HDL, (H) LDL, (I) adiponectin, (J) fasting insulin, (K) HOMA-IR, (L) NO, (M) GSH, (N) GSSG, and (O) GSH/GSSG. Values are mean ± S.D. (n=6), *P<0.05, **P<0.01 compared with normal group; ^#P<0.05, ^##P<0.01 compared with diabetic group; ^$$P<0.01 compared with Llirag group.

Figure 2. Effect of liraglutide on cardiac function in diabetic rats.

(A) SBP, (B) HR, (C) LVEDD, (D) LVESD, and (E) FS. n=6. **P<0.01 compared with control; ^##P<0.01 compared with diabetic.

Figure 3. Protein–protein interaction network in Hlirag group compared with diabetic group

The nods stand for differentially expressed genes in Hlirag group compared with diabetic group. The lines stand for the interactions between two proteins.

Figure 4. Confirmation of five representative differentially expressed genes by qPCR

Values are mean ± S.D. (n=6), **P<0.01 compared with normal group; ^##P<0.01 compared with diabetic group.

Figure 5. Liraglutide activates PPARα, which binds to RXR

Then PPARα inhibits its target gene, DGAT to inhibit oxidative stress. Liraglutide also activates Nr1h3 and SREBP and inhibits Angptl3 to activate LPL, leading the production of FFAs. Moreover, liraglutide inhibits sEH expression to increase EET.