Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC

• Published in: Atherosclerosis 2011-10, Vol.218 (2), p.431-434
• Main Authors: Ahrens, Ingo, Habersberger, Jonathon, Baumlin, Nadège, Qian, Hongwei, Smith, Belinda K, Stasch, Johannes-Peter, Bode, Christoph, Schmidt, Harald H.H.W, Peter, Karlheinz
• Format: Article
• Language: English
• Subjects: Aged; Atherosclerosis (general aspects, experimental research); BAY 58-2667; Benzoates - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Blood Platelets - drug effects; Blood Platelets - metabolism; Cardiology. Vascular system; Cardiovascular; Cell Adhesion Molecules - metabolism; Cinaciguat; Coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - metabolism; Coronary heart disease; Female; Guanylate Cyclase - blood; Heart; Heme - chemistry; Humans; Male; Medical sciences; Microfilament Proteins - metabolism; Middle Aged; Models, Biological; Oxidative Stress; Oxygen - chemistry; P-Selectin - blood; Phosphoproteins - metabolism; Phosphorylation; Platelets; sGC
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.06.042

Abstract Objective The soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient's oxidative burden. We here describe two platelet-based assays that allow determining the extent of oxidised sGC and thus provide a basis for an individualised pharmacotherapy. Methods/Results Platelets obtained from patients with ( n = 12) and without ( n = 12) coronary artery disease (CAD) were examined by flow cytometry (P-selectin expression), and Western blots (vasodilator associated phosphoprotein, VASP-phosphorylation). Results were compared to maximal oxidation of sGC achieved by the oxidising agent ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). Treatment of platelets with Cinaciguat resulted in differential activation of oxidised sGC. Platelet P-selectin expression and VASP-phosphorylation revealed significant differences ( p = 0.012, p = 0.039, respectively) between CAD and non-CAD patients. Conclusion We describe platelet-based assays that allow the determination of patients’ oxidative status and thus allow the prediction of pharmacological response to direct sGC activators.