Background Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with several treatment options. Long-term mortality remains high with great heterogeneity in treatment response. Even though most of the pathology of IPAH is observed in the lung, there is systemic involvement. Platelets from IPAH patients have characteristic metabolic shifts and defects in activation, therefore we investigated whether they could be used to identify other disease specific abnormalities. Methods We used proteomics to investigate protein expression changes in platelets from IPAH patients compared to healthy controls. Key abnormalities of nitric oxide pathway were tested in platelets from a larger cohort of unique IPAH patients. Results Platelets showed abnormalities in the prostacyclin and nitric oxide pathways, which are dysregulated in IPAH and hence targets of therapy. We detected reduced expression of G-protein as and increased expression of the regulatory subunits of the cAMP-dependent protein kinase (PKA) type II isoforms, supporting an overall decrease in the activation of the prostacyclin pathway. We noted reduced levels of the soluble guanylate cyclase (sGC) subunits and increased expression of the phosphodiesterase type 5A (PDE5A); conditions that affect the response to nitric oxide. Ensuing analysis of 38 unique patients with IPAH demonstrated considerable variation in the levels and specific activity of sGC, a finding with novel implications for personalized therapy. Interpretation Platelets have some of the characteristic vasoactive signal abnormalities seen in IPAH and may provide comprehensive ex-vivo mechanistic information to direct therapeutic decisions.

中文翻译：

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特发性肺动脉高压中疾病特异性血小板信号传导缺陷

背景 特发性肺动脉高压 (IPAH) 是一种进展迅速的疾病，有多种治疗选择。长期死亡率仍然很高，治疗反应的异质性很大。尽管在肺中观察到 IPAH 的大部分病理学，但也存在全身受累。IPAH 患者的血小板具有特征性的代谢变化和活化缺陷，因此我们研究了它们是否可用于识别其他疾病特异性异常。方法 我们使用蛋白质组学来研究与健康对照相比，IPAH 患者血小板中蛋白质表达的变化。一氧化氮通路的关键异常在来自更大的独特 IPAH 患者队列的血小板中进行了测试。结果血小板显示前列环素和一氧化氮通路异常，在 IPAH 中失调，因此是治疗的目标。我们检测到 G 蛋白的表达减少和 cAMP 依赖性蛋白激酶 (PKA) II 型亚型的调节亚基的表达增加，支持前列环素途径激活的总体减少。我们注意到可溶性鸟苷酸环化酶 (sGC) 亚基水平降低，5A 型磷酸二酯酶 (PDE5A) 表达增加；影响对一氧化氮反应的条件。随后对 38 名独特的 IPAH 患者的分析表明，sGC 的水平和特异性活性存在相当大的差异，这一发现对个性化治疗具有新的意义。