Resch Craig, Stamenkovic Aleksandra, Surendran Arun, Zhang Anran, Oudit Gavin Y, Shah Ashish, Ravandi Amir
Cardiovascular Lipidomics Laboratory, St. Boniface Hospital, Albrechtsen Research Centre, Manitoba, Canada; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada.
Mass Spectrometry Core Facility, BRIC-Rajiv Gandhi Centre for Biotechnology (RGCB), Kerala, India.
Free Radic Biol Med. 2025 Nov;239:219-229. doi: 10.1016/j.freeradbiomed.2025.07.042. Epub 2025 Jul 30.
Calcific aortic valve stenosis (CAVS) is a degenerative disease characterized by progressive calcification and narrowing of the aortic valve, driven by a multifactorial inflammatory process. Oxidized phospholipids (OxPL) have been implicated in CAVS pathogenesis, but their presence within aortic valve tissue remains poorly defined. In this study, we developed a sensitive 2,4-dinitrophenylhydrazine (DNPH)-based LC/MS/MS method to identify and quantify 60 individual OxPL species across five phospholipid classes in plasma and tissue samples from patients with severe CAVS. Aortic valve tissue was collected from 70 patients undergoing valve replacement surgery and compared with tissue from 20 healthy donors. We identified 32 distinct OxPL species, including oxidized phosphatidylcholine (OxPC), phosphatidylethanolamine (OxPE), phosphatidylinositol (OxPI), and phosphatidylserine (OxPS). OxPC was the most abundant class, with 1-palmitoyl-2-(9-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC) being the predominant species, accounting for 35 % of total OxPL. We observed a significant increase in 30 OxPL species with advancing disease severity, with the most pronounced changes occurring between early (healthy and mild) and advanced (moderate and severe) stages of CAVS. Specifically, PONPC levels increased by 90 % (p = 0.012), and total OxPC levels rose by 83 % (p = 0.004) from mild to moderate disease. Compared to healthy valves, OxPC levels increased by 123 % (p < 0.0001) in moderate CAVS and by 239 % (p = 0.02) in severe CAVS. However, OxPL levels did not significantly increase between moderate and severe stages. These findings suggest that OxPL accumulation in valve tissue is an early event in CAVS progression, supporting the rationale for early intervention with OxPL-lowering therapies as a potential strategy to mitigate disease advancement.
钙化性主动脉瓣狭窄（CAVS）是一种退行性疾病，其特征是主动脉瓣逐渐钙化和狭窄，由多因素炎症过程驱动。氧化磷脂（OxPL）与CAVS的发病机制有关，但其在主动脉瓣组织中的存在情况仍不明确。在本研究中，我们开发了一种基于2,4-二硝基苯肼（DNPH）的灵敏液相色谱/串联质谱（LC/MS/MS）方法，用于鉴定和定量重度CAVS患者血浆和组织样本中五类磷脂中的60种个体OxPL种类。从70例接受瓣膜置换手术的患者中收集主动脉瓣组织，并与20例健康供体的组织进行比较。我们鉴定出32种不同的OxPL种类，包括氧化磷脂酰胆碱（OxPC）、磷脂酰乙醇胺（OxPE）、磷脂酰肌醇（OxPI）和磷脂酰丝氨酸（OxPS）。OxPC是最丰富的类别，1-棕榈酰-2-（9-氧代壬酰基）-sn-甘油-3-磷酸胆碱（PONPC）是主要种类，占总OxPL的35%。我们观察到随着疾病严重程度的进展，30种OxPL种类显著增加，最明显的变化发生在CAVS的早期（健康和轻度）和晚期（中度和重度）阶段之间。具体而言，从轻度到中度疾病，PONPC水平增加了90%（p = 0.012），总OxPC水平上升了83%（p = 0.004）。与健康瓣膜相比，中度CAVS中OxPC水平增加了123%（p < 0.0001），重度CAVS中增加了239%（p = 0.02）。然而，OxPL水平在中度和重度阶段之间没有显著增加。这些发现表明，瓣膜组织中OxPL的积累是CAVS进展中的早期事件，支持了将降低OxPL疗法作为减轻疾病进展的潜在策略进行早期干预的基本原理。
