Objective To investigate the cardiovascular effect and mechanism of polyethylene glycol loxenatide (PEG-Loxe), a weekly preparation of glucagon like peptide-1 receptor agonist (GLP-1RAs), on apolipoprotein E gene knockout (ApoE^-/-) type 2 diabetes mellitus (T2DM) mice.

Methods Sixteen 8-week old male ApoE^-/- mice were randomly divided into two groups: T2DM group (8 mice) and PEG-Loxe intervention group (T2DM+Loxe group, 8 mice). The mice were fed with 109C diet. T2DM+Loxe group mice were intraperitoneally injected with PEG-Loxe every three days at a dose of 1 mg/kg body weight, and fed for 12 weeks. During this period, the weight and food intake of mice were recorded weekly, and the random blood glucoses were measured through tail vein. The 8 male C57/BL6j mice of the same age were selected as the blank control group (Ctrl group), and fed with regular feed. The mice were sacrificed upon expiration, and their serum and aorta were collected. The serum total cholesterol (TC), low-density lipoprotein (LDL) and receptor for advanced glycation end-products (RAGE) were measured using enzyme-linked immunosorbent assay. Immunohistochemistry was used to detect the staining of α-smooth muscle actin (α-SMA) and macrophage inflammatory cytokine glycoprotein (CD68) in the aortic root, Real-time PCR was used to detect RAGE mRNA expression and the Western blotting was used to detect RAGE protein expression.

Results The levels of blood glucose, TC and LDL in the T2DM+Loxe group were lower than those in T2DM group (P < 0.05). The expression of α-SMA protein in the aortic tissue of the T2DM+Loxe group was significantly higher than that of T2DM group, and the expression of CD68 was significantly lower than that of T2DM group. The expression of RAGE in the blood and aortic tissues of the T2DM+Loxe group was lower than that of T2DM group, and the difference was statistically significant (P < 0.05). The area of aortic plaques in the T2DM+Loxe group was lower than that in T2DM group, and the difference was statistically significant (P < 0.05).

Conclusions The PEG-Loxe can alleviate the progression of atherosclerosis in ApoE^-/- T2DM mice by reducing the glucose, LDL and RAGE expression, increasing the number of vascular smooth muscle cells, and reducing the macrophage deposition.