Liraglutide inhibited AGEs induced coronary smooth muscle cell phenotypic transition through inhibiting the NF-κB signal pathway.

Vascular smooth muscle cell (VSMC) phenotype transition is involved in diabetes-associated cardiovascular diseases. The mechanism of VSMCs phenotypic transition in T2DM was still unclear. Rat coronary artery SMCs were pretreated with liraglutide alone, liraglutide and H89(a PKA inhibitor), neutralizing anti-RAGE antibody or the antioxidant pyrrolidine dithiocarbamate (PDTC; a nuclear factor-κB (NF-κB) inhibitor), followed by treatment with AGE. The morphological change of the SMCs was observed. We also observed the α-actin positive myofilaments and F-actin distribution in SMC through immunofluorescence microscopy. Smooth muscle myosin heavy chain 11(MYH11), α-smooth muscle actin (α-SMA) and myocardin protein expression were detected by Western blot. Collagen I productionS and NF-κB nuclear translocation were also investigated. AGEs induced a transition of SMC from contractile to synthetic phenotype, which was associated with decreased SMC differentiation markers such as α-SMA, MYH11 and myocardin by activating the NF-κB pathway. AGE also increased collagen I production and secretion by SMCs. Liraglutide inhibited AGEs induced SM phenotypic transition and down-regulation of α-SMA, MYH11 and myocardin. Liraglutide also inhibited AGEs induced NF-κB pathway activation and collagen I production. Pretreatment with liraglutide and H89 together did not exhibit this inhibitory effect as mentioned above. Blockade of RAGE in SMCs with neutralizing antibody inhibited AGEs induced phenotypic transition of SMC, and up-regulated α-SMA and MYH11 expression. Liraglutide inhibited AGE induced SMC phenotypic transition, increased SMC contractile markers expression, and decreased collagen production through down-regulation of myocardin, inhibition of NF-κB pathway, and activation of PKA signaling pathway.