Thrombin Receptor PAR-4 is a Key Regulator of Exaggerated Intimal Thickening in Diabetes
Background—Diabetes predisposes to thrombotic and proliferative vascular remodeling, to which thrombin contributes via activation of protease-activated receptor PAR-1. Use of PAR-1 inhibitors to suppress remodeling may however be limited by severe bleeding. We recently reported upregulation of a further thrombin receptor, PAR-4, in human vascular smooth muscle cells (SMC) exposed to high glucose and have now examined PAR-4 as a novel mediator linking hyperglycemia, hypercoagulation and vascular remodeling in diabetes.
Methods and Results—PAR-4 expression was increased incarotid atherectomies and saphenous vein specimen from diabetic vs. non-diabetic patients, and in aorta and carotid arteries from streptozotocin-diabetic vs. non-diabetic C57BL/6 mice. Vascular PAR-1 mRNA was not increased in diabetic mice. Ligated carotid arteries from diabetic mice developed more extensive neointimal hyperplasia and showed greater proliferation than arteries from non-diabetic mice. The augmented remodeling response was absent in diabetic mice deficient in PAR-4. At the cellular level, PAR-4 expression was controlled via the mRNA stabilising actions of human antigen R, which accounted for the stimulatory actions of high glucose, angiotensin II and H2O2 on PAR-4 expression, while cicaprost via protein kinase A activation counteracted this effect.
Conclusions—PAR-4 appears to play a hitherto unsuspected role in diabetic vasculopathy. Development of PAR-4 inhibitors might serve to limit mainly proliferative processes in restenosis-prone diabetic patients, particularly those patients in whom severe bleeding due to selective PAR-1 blockade or complete thrombin inhibition must be avoided or who not require anticoagulation.
- Received November 18, 2013.
- Revision received August 22, 2014.
- Accepted September 11, 2014.