Impact of angiotensin-converting enzyme inhibition on platelet Tissue Factor expression in stroke-prone rats
ABSTRACT Objective: Hypertension is a well-known risk factor for thrombotic events such as myocardial infarction and stroke. Platelets express tissue factor (TF), the key activator of blood coagulation and thrombus formation. The number of TF-positive platelets increases in pathological conditions characterized by thrombotic complications but whether this occurs in hypertension is unknown. Here we investigated whether: 1) platelet TF expression is increased in a hypertensive status through a mechanism acting on megakaryocytes; 2) the phenomenon could be modulated by anti-hypertensive drug as captopril; 3) angiotensin influences platelet TF expression. Methods: SHRSP rats received standard diet (StD) or a high-salt permissive diet (JpD). After 3 weeks, JpD animals were randomized to receive captopril or vehicle. Normotensive Wistar Kyoto (WKY) rats were used as controls. Cell-associated TF expression and activity were analyzed by flow cytometry and Calibrated Automated Thrombogram, respectively. Results: Hypertensive StD-SHRSP showed an increased number of TF-positive platelet compared to normotensive WKY. After JpD administration, SHRSP developed severe hypertension and renal damage; the number of TF-positive megakaryocytes significantly increased compared to StD-SHRSP resulting in a higher number of TF-positive platelets with a faster kinetic of thrombin generation. These effects were reverted by captopril. Ex vivo stimulation of platelets, isolated from normotensive WKY and from healthy subjects, with angiotensin induced a concentration-dependent increase of surface-associated TF expression. Conclusion: This study shows for the first time that in hypertension the number of TF-positive megakaryocytes increases thus releasing in the circulation more platelets carrying a functionally active TF. Angiotensin stimulates platelets to express TF.