Impairment of Anti-Aggregatory Responses to Nitric Oxide and Prostacyclin: Mechanisms and Clinical Implications in Cardiovascular Disease

Figures

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  Figure 1. Schematic of endothelial/platelet interactions regarding GC/cGMP and AC/cAMP signalling and the impact of different disease states on anti-aggregatory responses to nitric oxide (NO) and prostacyclin (PGI2). Other abbreviations: AC = adenylate cyclase; Gs = stimulatory G-protein; IP-r = prostanoid IP receptor; PKA = cAMP-stimulated protein kinase; PKG = cGMP-stimulated protein kinase; SNP = sodium nitroprusside; sGC = soluble guanylate cyclase; VASP = vasodilator-stimulated phosphoprotein; VASP-P = phosphorylated VASP. Red stars define the sites of impaired signalling that are associated with different disease states and oxidative stress. The red arrows signify inhibitory impacts of various disease states: the black arrows imply progression through activation pathways.

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  Figure 2. Representative aggregation tracings displaying both an increased platelet aggregation response to ADP (2.5 µM) and a diminished inhibitory effect of sodium nitroprusside (SNP, 10 µM) in a coronary artery spasm (CAS) patient (inhibition of 9%) comparative to control subject (inhibition of 33%). Modified with permission from Reference [10].

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  Figure 3. Bases for variability in platelet soluble guanylate cyclase (sGC) functionality. sGC is a heterodimer that is composed of one α and one heme-binding β subunit. In its FeII form, this heme moiety is the target of nitric oxide (NO), either endogenous (synthesized by endothelium) or exogenous. The binding of NO to the heme results in the activation of the catalytic domain, which produces cGMP from GTP. In conditions of oxidative stress, heme is oxidized to FeIII form, which has a lesser affinity for NO, resulting in diminished activation of sGC (“NO resistance”) and a loss of the heme moiety. Within platelets, there is a heterogeneity of the sGC molecular state (reduced, oxidized, and heme-deficient). The overall platelet responsiveness to NO in vivo reflects the relative prevalence of each of these sGC states.