Abstract
Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir) is considered a potential alternative. We recently developed an Ir(III)-derived complex, [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-11), which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP) release, intracellular Ca2+ mobilization, P-selectin expression, and OH· formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2–PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells.
Highlights
Intravascular thrombosis is a cause of various cardiovascular diseases (CVDs)
We further examined the effect of Ir-11 on the phosphorylation of the phospholipase Cγ2 (PLCγ2)-protein kinase C (PKC) signaling cascade
A study demonstrated that Jun N-terminal kinases (JNKs)−/− platelets are associated with an increased bleeding time, decreased integrin αIIbβ3 activation, and severe granule secretion impairment [25]. In accordance with these findings, the present results demonstrated that Ir-11 markedly inhibits the collagen-induced phosphorylation of these three mitogen-activated protein kinases (MAPKs)
Summary
Intravascular thrombosis is a cause of various cardiovascular diseases (CVDs). The growth of thrombus inside the stent lumen is the outcome of platelet adhesion, and platelet activation followed by platelet aggregation. Platelets play a crucial role in the pathogenesis of CVDs, including coronary artery disease and stroke [1]. The release of several mediators (e.g., adenosine triphosphate (ATP) and thromboxane A2) occurs in conjunction with relative intracellular Ca2+ ([Ca2+]i) mobilization; these processes attract additional platelets toward the injured endothelium, and cause thickening of the initial platelet monolayer. Fibrinogen binds to its specific platelet receptor (integrin αIIbβ3), completing the final common pathway for platelet aggregation. Platelets are activated via high-affinity and low-affinity hypersensitivity receptors, which can induce Kounis hypersensitivity-associated thrombotic syndrome
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call