Abstract 13351: Impaired Contractile Responses to Thromboxane A2 of Peripheral Arterioles from Patients with Uncontrolled Diabetes
Background: We compared the contractile response of skeletal muscle arterioles to TXA2, and the related signaling pathway in patients with controlled, uncontrolled diabetes and case-matched non-diabetes.
Methods: Skeletal muscle arterioles (90-180 µm in diameter) were harvested from patients with controlled diabetes (n=10, HbA1C=6.3±0.15), uncontrolled diabetes (n=10, HbA1C=9.0±0.3), and case-matched non-diabetics(n =10, HbA1C = 5.2 ± 0.1) undergoing cardiac surgery. Videomicroscopy was used to measure microvascular constriction in response to TXA2 analog U-46619 with and without a TXA2 receptor antagonist, phospholipase C (PLC) inhibitors, or phospholipase A-2 (PLA-2)inhibitor or PKC inhibitor. The gene and protein expressions of TXA-2 related signaling in the skeletal muscle were measured by microarray analysis and western blotting.
Results: The contractile response to U-46619 (10-6M) of uncontrolled, but not well-controlled diabetic arterioles, was significantly decreased compared with those of non-diabetics (P<0.05). The contractile responses of diabetic and non-diabetic arterioles to U-46619 were significantly diminished in the presence of either the TXA2 receptor antagonist SQ-29548 (10-6M) or the PLC inhibitor U-73122 (10-6M, P<0.05). Administration of either the PLA-2 inhibitor quanacrine (10-7M) or PKC inhibitor safingol (2x10-5M) also inhibited U46619-induced constriction of arterioles from patients with controlled or uncontrolled diabetes, but failed to affect U-46619-induced constriction of arterioles from non-diabetics. Surprisingly, there were no significant changes in the expression of genes related TXA-2 signaling in diabetic or non-diabetic groups. In contrast, protein expression of TXA-2 receptors and PLC was decreased in the uncontrolled diabetic compared to the non-diabetic patients.
Conclusion: Skeletal muscle arterioles from poorly controlled, but not well controlled diabetic patients demonstrated vasomotor dysfunction and TXA2 related protein down-regulation. The contractile responseof diabetic arterioles to TXA2 is via activation of TXA2 receptors, PLC, PLA-2, and PKC, whereas the response of non-diabetic vessels is only via activation of TXA2 and PLC.
- © 2011 by American Heart Association, Inc.