Goran Pavic1, Maria Grandoch1, Seema Dangwal1, Klaus Jobi1, Bernhard H Rauch1, Anke Doller1, Alexander Oberhuber1, Payam Akhyari1, Karsten Schrör1, Jens W Fischer1, Anke C Fender2. 1. From the Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany (G.P., M.G., K.J., K.S., J.W.F., A.C.F.); Institute of Molecular and Translational Therapeutic Strategies, Medizinische Hochschule, Hannover, Germany (S.D.); Institut für Pharmakologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany (B.H.R.); Klinikum der J. W. Goethe Universität, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt/Main, Germany (A.D.); Klinik für Gefäß und Endovaskularchirurgie (A.O.) and Klinik für Kardiovaskuläre Chirurgie (P.A.), Klinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. 2. From the Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany (G.P., M.G., K.J., K.S., J.W.F., A.C.F.); Institute of Molecular and Translational Therapeutic Strategies, Medizinische Hochschule, Hannover, Germany (S.D.); Institut für Pharmakologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany (B.H.R.); Klinikum der J. W. Goethe Universität, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt/Main, Germany (A.D.); Klinik für Gefäß und Endovaskularchirurgie (A.O.) and Klinik für Kardiovaskuläre Chirurgie (P.A.), Klinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. anke.fender@uni-duesseldorf.de.
Abstract
BACKGROUND: Diabetes mellitus predisposes to thrombotic and proliferative vascular remodeling, to which thrombin contributes via activation of protease-activated receptor (PAR) 1. However, the use of PAR-1 inhibitors to suppress remodeling may be limited by severe bleeding. We recently reported upregulation of an additional thrombin receptor, PAR-4, in human vascular smooth muscle cells exposed to high glucose and have now examined PAR-4 as a novel mediator linking hyperglycemia, hypercoagulation, and vascular remodeling in diabetes mellitus. METHODS AND RESULTS: PAR-4 expression was increased in carotid atherectomies and saphenous vein specimens from diabetic versus nondiabetic patients and in aorta and carotid arteries from streptozotocin-diabetic versus nondiabetic 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 nondiabetic 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 stabilizing actions of human antigen R, which accounted for the stimulatory actions of high glucose, angiotensin II, and H2O2 on PAR-4 expression, whereas cicaprost via protein kinase A activation counteracted this effect. CONCLUSIONS: PAR-4 appears to play a hitherto unsuspected role in diabetic vasculopathy. The development of PAR-4 inhibitors might serve to limit mainly proliferative processes in restenosis-prone diabetic patients, particularly those patients in whom severe bleeding attributed to selective PAR-1 blockade or complete thrombin inhibition must be avoided or those who do not require anticoagulation.
BACKGROUND:Diabetes mellitus predisposes to thrombotic and proliferative vascular remodeling, to which thrombin contributes via activation of protease-activated receptor (PAR) 1. However, the use of PAR-1 inhibitors to suppress remodeling may be limited by severe bleeding. We recently reported upregulation of an additional thrombin receptor, PAR-4, in human vascular smooth muscle cells exposed to high glucose and have now examined PAR-4 as a novel mediator linking hyperglycemia, hypercoagulation, and vascular remodeling in diabetes mellitus. METHODS AND RESULTS:PAR-4 expression was increased in carotid atherectomies and saphenous vein specimens from diabetic versus nondiabeticpatients and in aorta and carotid arteries from streptozotocin-diabetic versus nondiabetic C57BL/6 mice. Vascular PAR-1 mRNA was not increased in diabeticmice. Ligated carotid arteries from diabeticmice developed more extensive neointimal hyperplasia and showed greater proliferation than arteries from nondiabetic mice. The augmented remodeling response was absent in diabeticmice deficient in PAR-4. At the cellular level, PAR-4 expression was controlled via the mRNA stabilizing actions of human antigen R, which accounted for the stimulatory actions of high glucose, angiotensin II, and H2O2 on PAR-4 expression, whereas cicaprost via protein kinase A activation counteracted this effect. CONCLUSIONS:PAR-4 appears to play a hitherto unsuspected role in diabetic vasculopathy. The development of PAR-4 inhibitors might serve to limit mainly proliferative processes in restenosis-prone diabeticpatients, particularly those patients in whom severe bleeding attributed to selective PAR-1 blockade or complete thrombin inhibition must be avoided or those who do not require anticoagulation.
Authors: Anke C Fender; Sonja Kleeschulte; Svenja Stolte; Katja Leineweber; Markus Kamler; Johannes Bode; Na Li; Dobromir Dobrev Journal: Basic Res Cardiol Date: 2020-01-07 Impact factor: 17.165
Authors: Robert H Lee; Tomohiro Kawano; Steven P Grover; Vanthana Bharathi; David Martinez; Dale O Cowley; Nigel Mackman; Wolfgang Bergmeier; Silvio Antoniak Journal: J Thromb Haemost Date: 2021-11-10 Impact factor: 5.824
Authors: M J Whitley; D M Henke; A Ghazi; M Nieman; M Stoller; L M Simon; E Chen; J Vesci; M Holinstat; S E McKenzie; C A Shaw; L C Edelstein; P F Bray Journal: J Thromb Haemost Date: 2018-11-22 Impact factor: 5.824