Institute of Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Sandwell and West Birmingham NHS Trust, City Hospital, Birmingham B18 7QH, UK.
Cardiovasc Res. 2018 Aug 1;114(10):1313-1323. doi: 10.1093/cvr/cvy087.
Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared with healthy volunteers (HVs) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF-AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood.
Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF-AF patients (n = 29), and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared with healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP.
We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the 'platelet NO resistance' phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO.
心力衰竭（HF）是一种促血栓形成状态。由于一氧化氮（NO）供体的清除，以及主要的 NO 传感器可溶性鸟苷酸环化酶（sGC）的活性可能降低，与健康志愿者（HV）相比，射血分数降低的心力衰竭（HFrEF）患者的血小板和血管对 NO 供体的反应受损，限制了 NO 供体作为抗聚集剂的治疗潜力。先前的研究表明，亚硝酸盐假定在还原为 NO 后抑制血小板激活，但涉及的机制仍知之甚少。我们的目的是比较亚硝酸盐对射血分数保留的心力衰竭（HFpEF）伴慢性心房颤动（HFpEF-AF）患者、慢性 AF 无 HF 患者与 HV 患者血小板功能的影响，并评估这些影响是否独立于与血液其他形成成分的相互作用而发生。
在年龄匹配的 HV 对照组（n=12）、HFpEF-AF 患者（n=29）和慢性 AF 患者（n=8）中比较了亚硝酸盐和一氧化氮供体硝普钠（SNP）对血小板反应的影响。在存在 NO 清除剂/sGC 抑制剂的情况下，测定了亚硝酸盐的抗聚集作用，并使用 Western blot 评估了血管扩张刺激磷蛋白（VASP）磷酸化。在 HV 和慢性 AF 中，亚硝酸盐和 SNP 均以浓度依赖性方式抑制血小板聚集。与健康人和慢性 AF 个体相比，HFpEF-AF 患者中 NO 供体 SNP 抑制血小板聚集的作用受损，但亚硝酸盐的抗聚集作用不受影响。亚硝酸盐通过直接激活 sGC 和磷酸化 VASP，绕过血小板的 NO 抵抗，独立于其他血细胞。
我们首次表明，HFpEF-AF（而非无 HF 的慢性 AF）与 sGC 功能障碍导致的血小板 NO 反应明显受损有关，并且亚硝酸盐至少部分通过作为一种独立于 NO 的直接 sGC 激活剂，绕过人 HFpEF 中的“血小板 NO 抵抗”现象。
