Sverdlov Aaron L, Chan Wai P A, Procter Nathan E K, Chirkov Yuliy Y, Ngo Doan T M, Horowitz John D
Cardiology Unit, Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia.
Int J Cardiol. 2013 Oct 12;168(5):4624-30. doi: 10.1016/j.ijcard.2013.07.159. Epub 2013 Jul 25.
Impaired tissue responsiveness to nitric oxide (NO) occurs in many cardiovascular diseases as well as with advanced age and is a correlate of poor outcomes. This phenomenon results from oxidative stress, with NO "scavenging" and dysfunction of soluble guanylate cyclase (sGC). Thioredoxin-interacting protein (TXNIP) is a major intracellular regulator of inflammatory activation and redox stress, but its interactions with NO/sGC are poorly understood. We have now evaluated the relationship between platelet TXNIP expression and function of the NO/sGC axis in subjects of varying age and during therapy with ramipril.
METHODS & RESULTS: Young (n=42) and aging (n=49) subjects underwent evaluation of platelet TXNIP content. Aging subjects additionally had measurements of platelet NO responsiveness and routine biochemistry. Platelet TXNIP content was greater (376±33 units) in the aging compared to younger subjects (289±13 units; p<0.05). In the aging subjects there was a significant negative correlation (r=-0.50, p<0.001) between platelet TXNIP content and NO responsiveness. In a separate cohort of 15 subjects two week treatment with ramipril, which reversed platelet NO resistance and potentiated sGC activity, also decreased platelet TXNIP content by 40% (p=0.011).
Platelet TXNIP content increases with aging, varies inversely with responsiveness to NO, and diminishes rapidly following treatment with ramipril. These data suggest that TXNIP-induced oxidative stress may be a critical modulator of tissue resistance to NO, a fundamental basis for cardiovascular disease. Analogously suppression of TXNIP expression can potentially be utilized as an index of restoration of cardiovascular homeostasis.
组织对一氧化氮（NO）的反应性受损在许多心血管疾病以及高龄人群中均有发生，并且与不良预后相关。这种现象是由氧化应激导致的，会出现NO“清除”以及可溶性鸟苷酸环化酶（sGC）功能障碍。硫氧还蛋白相互作用蛋白（TXNIP）是炎症激活和氧化还原应激的主要细胞内调节因子，但其与NO/sGC的相互作用尚不清楚。我们现在评估了不同年龄受试者以及接受雷米普利治疗期间血小板TXNIP表达与NO/sGC轴功能之间的关系。
年轻受试者（n = 42）和老年受试者（n = 49）接受了血小板TXNIP含量评估。老年受试者还进行了血小板NO反应性测量和常规生化检查。与年轻受试者（289±13单位）相比，老年受试者的血小板TXNIP含量更高（376±33单位；p<0.05）。在老年受试者中，血小板TXNIP含量与NO反应性之间存在显著负相关（r = -0.50，p<0.001）。在另一组15名受试者中，为期两周的雷米普利治疗逆转了血小板对NO的抵抗并增强了sGC活性，同时血小板TXNIP含量也降低了40%（p = 0.011）。
血小板TXNIP含量随年龄增长而增加，与对NO的反应性呈负相关，并且在雷米普利治疗后迅速降低。这些数据表明，TXNIP诱导的氧化应激可能是组织对NO抵抗的关键调节因子，是心血管疾病的一个基本基础。类似地，抑制TXNIP表达可能被用作心血管稳态恢复的指标。
