摘要：

Monocyte hyperactivation as seen in diabetes results in increased cytoskeletal rigidity and reduced cell deformability leading to microchannel occlusions and microvascular complications. The thiazolidinediones (TZDs) are PPAR-γ agonists that have been reported to exert beneficial non-metabolic effects on the vasculature. This study demonstrates that the TZD, Rosiglitazone, significantly reduces f-MLP-induced actin polymerisation in human monocytic cells (p&#xa0;<&#xa0;0.05). Two of the key signalling processes known to be involved in the regulation of cytoskeletal remodelling were investigated: PI3K-dependent Akt phosphorylation and intracellular calcium concentration [Ca2+]i. The PI3K inhibitor, Wortmannin, ameliorated f-MLP-induced actin polymerisation (p&#xa0;<&#xa0;0.05), while the Ca2+ sequestration inhibitor, thapsigargin, induced actin depolymerisation (p&#xa0;<&#xa0;0.05), confirming the involvement of both processes in cytoskeletal remodelling. Rosiglitazone significantly reduced f-MLP activation of Akt (p&#xa0;<&#xa0;0.05), and significantly increased [Ca2+]i in both resting and f-MLP-stimulated cells (p&#xa0;<&#xa0;0.05). Therefore, Rosiglitazone interacts with signalling events downstream of occupancy of the f-MLP receptor, to modulate cytoskeletal remodelling in a PPAR-γ-independent manner. To our knowledge, these results are the first to present evidence that a PPAR-γ agonist can modulate actin remodelling in monocytes, and may therefore be protective against microvascular damage in diabetes.

展开