Reciprocal regulation of NO signaling and TXNIP expression in humans: Impact of aging and ramipril therapy

Aaron Sverdlov, Wai Chan, Nathan Procter, Yuliy Chirkov, Doan Ngo, John Horowitz

    Research output: Contribution to journalArticlepeer-review

    22 Citations (Scopus)

    Abstract

    Background 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). Conclusions 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.

    Original languageEnglish
    Pages (from-to)4624-4630
    Number of pages7
    JournalInternational Journal of Cardiology
    Volume168
    Issue number5
    DOIs
    Publication statusPublished - 12 Oct 2013

    Keywords

    • ACE inhibitors
    • Aging
    • Nitric oxide
    • Platelets
    • Thioredoxin-interacting protein

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