FABP4 Induces Vascular Smooth Muscle Cell Proliferation and Migration through a MAPK-Dependent Pathway

Abstract

PurposeThe migration and proliferation of vascular smooth muscle cells play crucial roles in the development of atherosclerotic lesions. This study examined the effects of fatty acid binding protein 4 (FABP4), an adipokine that is associated with cardiovascular risk, endothelial dysfunction and proinflammatory effects, on the migration and proliferation of human coronary artery smooth muscle cells (HCASMCs). Methods and ResultsA DNA 5-bromo-2′-deoxy-uridine (BrdU) incorporation assay indicated that FABP4 significantly induced the dose-dependent proliferation of HCASMCs with a maximum stimulatory effect at 120 ng/ml (13% vs. unstimulated cells, p<0.05). An anti-FABP4 antibody (40 ng/ml) significantly inhibited the induced cell proliferation, demonstrating the specificity of the FABP4 proliferative effect. FABP4 significantly induced HCASMC migration in a dose-dependent manner with an initial effect at 60 ng/ml (12% vs. unstimulated cells, p<0.05). Time-course studies demonstrated that FABP4 significantly increased cell migration compared with unstimulated cells from 4 h (23%vs. 17%, p<0.05) to 12 h (74%vs. 59%, p<0.05). Pretreatment with LY-294002 (5 µM) and PD98059 (10 µM) blocked the FABP4-induced proliferation and migration of HCASMCs, suggesting the activation of a kinase pathway. On a molecular level, we observed an up-regulation of the MAPK pathway without activation of Akt. We found that FABP4 induced the active forms of the nuclear transcription factors c-jun and c-myc, which are regulated by MAPK cascades, and increased the expression of the downstream genes cyclin D1 and MMP2, CCL2, and fibulin 4 and 5, which are involved in cell cycle regulation and cell migration. ConclusionsThese findings indicate a direct effect of FABP4 on the migration and proliferation of HCASMCs, suggesting a role for this adipokine in vascular remodelling. Taken together, these results demonstrate that the FABP4-induced DNA synthesis and cell migration are mediated primarily through a MAPK-dependent pathway that activates the transcription factors c-jun and c-myc in HCASMCs.

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

“…B1 repetitive elements are the sequences of short interspersed nucleotide elements in mice, corresponding to the Alu sequence in humans (19). Increasing evidence suggests that B1 repetitive element hypomethylation is associated with gene transcriptional activity in the pathogenesis of cardiovascular diseases, particularly AS (43). In the present study, it was also found that B1 repetitive elements exhibited hypomethylation in the blood cells of the AS model.…”

Differential Protein Expression in White Adipose Tissue from Obesity-Prone and Obesity-Resistant Mice in Response to High Fat Diet and Anti-Obesity Herbal Medicines

“…Although the biological role of FABP4 is not fully understood, it has been linked to insulin sensitivity, lipid metabolism, and inflammation [46]. Previously, we have shown that FABP4 levels are elevated in obese and diabetic individuals, and such increased levels are closely correlated with adverse lipid profiles, insulin resistance, and vascular smooth muscle cell proliferation [47,48,49,50]. In this study, protein and mRNA expression of FABP4 were reduced in OR and TH mice, which suggests alleviation of fat accumulation in adipocytes.…”

Fatty Acid Binding Protein 4 Deficiency Protects against Oxygen-Induced Retinopathy in Mice

“…Exogenous administration of FABP4 was able to induce smooth muscle cell proliferation and chemokinesis in vitro [38]. Therefore we considered the possibility that circulating FABP4 could contribute to pathological retinal neovascularization.…”