The renin-angiotensin system in healthy human platelets: expressed but inactive

Platelets play a crucial role in arterial thrombus formation, offering potential for new antiplatelet therapies with reduced bleeding risk. Here, we investigated the role of the renin-angiotensin system (RAS) in human platelets and explored its potential link to COVID-19 coagulopathy. Experiments were performed <i>ex vivo</i> on healthy human platelets. The expression of RAS receptors (Mas, MrgD, ACE, ACE2, AT1 and AT2) was evaluated using western blot and immunofluorescence. Platelets were incubated <i>in vitro</i> with either Captopril or different RAS peptides including Alamandine, Angiotensin-I, Angiotensin-II, Angiotensin-(1–7), and Angiotensin-(1–9). Platelet adhesion was measured by spectrophotometry using BCECF fluorescence. Platelet activation and aggregation were analyzed using aggregometry after stimulation with extracellular matrix proteins. ACE and ACE2 activity were assessed using Fluorescent Peptides (FPS). We demonstrated that healthy human platelets express all the tested RAS receptors. However, RAS peptides did not modulate platelet adhesion or aggregation despite a wide range of concentrations tested. ACE activity was detected in platelet lysates, but it was not inhibited by Captopril, while ACE2 activity was undetectable. Our findings suggest that while RAS receptors are expressed in platelets, RAS peptides do not impact platelet function, at least in our experimental setting. COVID-19 coagulopathy may occur independently of the RAS. Platelets play a crucial role in the formation of a blood clot after vessel injury. However, blood clots can also obstruct arteries ( = arterial thrombosis), resulting in heart attack, stroke, or peripheral ischemia. As platelets play such an important role in the pathological development of arterial thrombosis, antiplatelet therapies aim to reduce the risk of recurrence of these diseases. Antiplatelet therapies usually work by targeting specific receptors to reduce platelet activity, i.e. platelet adhesion, aggregation and activation. As current antiplatelet agents can cause bleeding, research aims to develop new strategies to target only pathological platelet conditions. In this study, we tried to characterize the effect of different peptides belonging to the renin-angiotensin system (RAS) on platelets. As the RAS plays an important role in blood pressure regulation, we sought to establish whether it also plays a role in platelet activity. Furthermore, as SARS-CoV-2 usually enters cells via ACE2, an enzyme belonging to the RAS, we questioned whether the RAS could play a role in peripheral thrombosis associated with severe COVID-19 disease (COVID-19 coagulopathy). We observed that RAS receptors are expressed by platelets, while RAS peptides did not affect platelet adhesion, aggregation, and activation in our experiments. Consequently, we do not think that the RAS plays a significant role in platelet dynamics and COVID-19 coagulopathy.