The NO/cGMP/PKG pathway in platelets: The therapeutic potential of PDE5 inhibitors in platelet disorders

Abstract

Platelets are the “guardians” of the blood circulatory system. At sites of vessel injury, they ensure hemostasis and promote immunity and vessel repair. However, their uncontrolled activation is one of the main drivers of thrombosis. To keep circulating platelets in a quiescent state, the endothelium releases platelet antagonists including nitric oxide (NO) that acts by stimulating the intracellular receptor guanylyl cyclase (GC). The latter produces the second messenger cyclic guanosine‐3′,5′‐monophosphate (cGMP) that inhibits platelet activation by stimulating protein kinase G, which phosphorylates hundreds of intracellular targets. Intracellular cGMP pools are tightly regulated by a fine balance between GC and phosphodiesterases (PDEs) that are responsible for the hydrolysis of cyclic nucleotides. Phosphodiesterase type 5 (PDE5) is a cGMP‐specific PDE, broadly expressed in most tissues in humans and rodents. In clinical practice, PDE5 inhibitors (PDE5i) are used as first‐line therapy for erectile dysfunction, pulmonary artery hypertension, and lower urinary tract symptoms. However, several studies have shown that PDE5i may ameliorate the outcome of various other conditions, like heart failure and stroke. Interestingly, NO donors and cGMP analogs increase the capacity of anti‐platelet drugs targeting the purinergic receptor type Y, subtype 12 (P2Y12) receptor to block platelet aggregation, and preclinical studies have shown that PDE5i inhibits platelet functions. This review summarizes the molecular mechanisms underlying the effect of PDE5i on platelet activation and aggregation focusing on the therapeutic potential of PDE5i in platelet disorders, and the outcomes of a combined therapy with PDE5i and NO donors to inhibit platelet activation.

Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

“…Nitric oxide is a key signaling molecule in endothelium to act as vasodilator factor, generated by nitric oxide synthase (NOS) ( 78 ). Endothelial production of NO can inhibit multiple events during AS, such as inhibiting ECs activation, macrophage infiltration ( 79 ), foam cell formation/migration ( 80 ), platelet aggregation ( 81 ), inflammation ( 82 ), thrombosis ( 83 ), vascular wall remodeling ( 84 ), and mediating vasodilation ( 85 ). The mechanism of Hcy disturbance of NO synthesis is relatively complex, asymmetric dimethylarginine (ADMA) plays an important role in it, which is an endogenous inhibitor of NOS.…”

Platelets and Cardioprotection: The Role of Nitric Oxide and Carbon Oxide

“…NO regulates cGMP levels and the cGMP inhibitory effects predominantly depend on the PKG, the major effector of cGMP signaling in the cardiovascular system [ 49 , 50 , 51 , 52 , 53 ] ( Figure 1 ).…”

PDE5A: Key Enzyme to Overcome Platelet Inhibition

“…7 Interestingly, several preclinical studies have shown beneficial effects of PDE5 inhibitors in the treatment of diseases where platelets play essential roles. 7…”

“…6,7 Understanding how cGMP degradation contributes to platelet function is clinically relevant as selective PDE5 inhibitors (e.g., sildenafil and tadalafil) are used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain lower urinary tract symptoms. 7 Interestingly, several preclinical studies have shown beneficial effects of PDE5 inhibitors in the treatment of diseases where platelets play essential roles. 7 In this issue of Thrombosis and Haemostasis, Gui et al provide genetic evidence of the role of PDE5A in platelet function and thrombus formation using a constitutive KO mouse model.…”

“…7 Interestingly, several preclinical studies have shown beneficial effects of PDE5 inhibitors in the treatment of diseases where platelets play essential roles. 7 In this issue of Thrombosis and Haemostasis, Gui et al provide genetic evidence of the role of PDE5A in platelet function and thrombus formation using a constitutive KO mouse model. 8 cGMP levels in resting PDE5A KO platelets were moderately elevated, correlating with minor defects in aggregation.…”