Abstract 664: Vascular Smooth Muscle Toll-like Receptor-2 (tlr2) Is Upregulated During Hyperglycemia
Hyperglycemia, the major initiator of diabetic vascular dysfunction, is related with heightened vascular contractility and inflammation. Toll-like receptor-2 (TLR2), a key effector of innate immunity, has recently emerged as a crucial mediator of proinflammatory signaling during diabetes; however, whether or not TLR2 is altered during diabetic vascular complications remains to be elucidated. We hypothesize that upregulation of TLR2 contributes to vascular dysfunction and inflammation in the aorta of diabetic rats. This study was performed in streptozotocin (STZ)-induced diabetic rats (65mg/kg; 5 weeks) and primary aortic vascular smooth muscle cell (VSMC) cultures stimulated with high glucose (HG; 25mM), in vivo and in vitro models of hyperglycemia, respectively. To confirm the diabetic vascular dysfunction condition, myograph studies were performed. The results showed that thoracic aortic rings from STZ-induced diabetic rats have increased contractile response to phenylephrine (PE, 1ηM to 0.1mM) compared to control (Emax 206.20%±8.99% vs 98.41%±3.65%, respectively). TLR2 was increased significantly in the aorta from STZ-induced diabetic rats (1.8 fold vs. control) and in aortic VSMCs stimulated with HG for 6 hours (1.5 fold vs control). Elevated tumor necrosis factor α (TNF-α) and decreased interleukin-10 (IL-10) protein levels confirmed the proinflammatory state of aortas from STZ-diabetic rats (2.5 and 0.4 fold vs. control, respectively). Furthermore, expression of MyD88, a downstream adaptor protein for TLR2 signaling, is augmented significantly in diabetic aorta and aortic VSMCs under HG conditions (2.6 and 1.5 fold vs. control, respectively). Also, considering that protein kinase C (PKC) is a potential candidate of upstream activation of TLR2, we evaluated the expression the PKC isoforms. Our results show that PKCε is the only isoform increased significantly (1.7 fold vs. control). Our findings suggest that activating TLR2/MyD88 signaling pathway may play a role in mediating augmented proimflammatory response, which in turn contributes to vascular dysfunction during hyperglycemic conditions.
- © 2012 by American Heart Association, Inc.