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

Abstract

Nitric oxide (NO) and carbon monoxide (CO) represent a pair of biologically active gases with an increasingly well-defined range of effects on circulating platelets. These gases interact with platelets and cells in the vessels and heart and exert fundamentally similar biological effects, albeit through different mechanisms and with some peculiarity. Within the cardiovascular system, for example, the gases are predominantly vasodilators and exert antiaggregatory effects, and are protective against damage in myocardial ischemia-reperfusion injury. Indeed, NO is an important vasodilator acting on vascular smooth muscle and is able to inhibit platelet activation. NO reacts with superoxide anion (O₂(^-•)) to form peroxynitrite (ONOO(^-)), a nitrosating agent capable of inducing oxidative/nitrative signaling and stress both at cardiovascular, platelet, and plasma levels. CO reduces platelet reactivity, therefore it is an anticoagulant, but it also has some cardioprotective and procoagulant properties. This review article summarizes current knowledge on the platelets and roles of gas mediators (NO, and CO) in cardioprotection. In particular, we aim to examine the link and interactions between platelets, NO, and CO and cardioprotective pathways.

Keywords: gasotransmitters; nitrosating agents; platelets; preconditioning; remote conditioning.

Figure 1

(A). Nitric oxide (NO) in blood vessels is mainly synthetized by endothelial nitric oxide synthase (eNOS), expressed by endothelial cells (ECs), and it is enhanced by stimuli such as insulin and shear stress. Platelets could also express eNOS, representing, therefore, another source of NO in the blood stream. (B). In platelets, NO enhances guanosine 3’,5’-cyclic monophosphate (cGMP) synthesis through the activation of soluble guanylate cyclase (sGC). cGMP activates phosphodiesterase 3 (PDE3) and PDE2 activity, modulating platelet cyclic adenosine monophosphate (cAMP) levels. cGMP activates PKG, leading to the activation of PDE5 and reduction of cGMP levels, and is responsible for the phosphorylation of many substrates involved in mechanisms of inhibition of platelet activity, including intracellular Ca²⁺ release. Similarly, CO also stimulates the activation of sGC and inhibits Ca²⁺ entry.

Figure 2

Mitochondrial permeability transition pore (MPTP) opening is the main end effector in ischemia reperfusion injury (IRI). On one side, platelets contribute to IRI mainly by microthrombi formation and platelet-leukocyte aggregates (PLAs). On the other side, molecules of platelet origin, such as platelet activating factor phosphoglyceride (PAF) and sphingosine-1-phosphate (S1P), lead to the activation of cardioprotective pathways, such as the reperfusion injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) pathway, all targeting inhibition of MPTP opening. Besides, the interaction between platelets and gasotransmitters has a central role in cardioprotection. Nitric oxide (NO) activates the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) pathway, leading to the inhibition of platelet adhesion, activation, and aggregation. NO can inhibit platelet response also by cGMP-independent mechanisms. NO inhibitory effect on platelets is reduced in the presence of increased levels of reactive oxygen species (ROS). Also, PKG leads to the opening of the mitochondrial ATP-dependent K+ channel (mitoKATP) and subsequent inhibition of MPTP. Carbon monoxide (CO) exerts its cardioprotective action triggering the opening of mitoKATP with consequent inhibition of the opening of MPTP and modulating mitochondrial ROS production. Furthermore, it can inhibit platelet activation both by cGMP-dependent and cGMP-independent mechanisms.