Introduction Patients with Type 2 diabetes mellitus (T2DM) suffer premature cardiovascular disease and poor prognosis after revascularisation procedures. Following saphenous vein bypass grafting, smooth muscle cell (SMC) plasticity is vital to graft adaptation and subsequent patency. We recently demonstrated that T2DM-SMC exhibit an aberrant phenotype distinct from non-diabetic (ND)-SMC which is driven by increased expression of microRNAs miR−143 and −145. This study investigated potential diabetic stimuli that modulate miR-143/145 and alter SMC phenotype.
Methods Cultured ND-SMC were exposed to candidate stimuli (glucose, insulin, inflammatory cytokines, transforming growth factor beta [TGFβ]) for 48h. SMC morphology (area, F-actin staining), function (proliferation) and miR-143/145 expression (real-time RT-PCR) were subsequently evaluated. Mechanisms were explored using antimiR transfection and/or neutralising antibodies.
Results Only exposure to TGFβ promoted a robust T2DM phenotype in ND cells; i.e. increased miR-143/145 (p<0.001), increased cell area (p<0.05), disrupted F-actin and reduced proliferation (p<0.05, all n=5), effects that were reversed by antimiR-143/145 transfection (p<0.01, n=6). However, treatment of T2DM-SMC with TGFβ receptor (TGFβRII) neutralising antibody did not reinstate ND characteristics (n=4).
Conclusion TGFβ confers a T2DM phenotype in ND-SMC that is driven by upregulation of miR-143/145. Interestingly, inhibition of TGFβ signalling per se did not restore a ND phenotype in T2DM-SMC suggesting that previous in vivo exposure of SMC to elevated circulating levels of TGFβ may be the perpetrator of persistent changes in phenotype and function that are not easily reversed. These observations support the notion of “metabolic memory”, a phenomenon likely to be epigenetic in nature and currently under investigation.
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