1. Reciprocal regulation of NO signaling and TXNIP expression in humans: impact of aging and ramipril therapy
- Author
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Nathan E.K. Procter, Doan T.M. Ngo, Yuliy Y. Chirkov, John D. Horowitz, Wai P.A. Chan, Aaron L. Sverdlov, Sverdlov, AL, Chan, WPA, Procter, NEK, Chirkov, YY, Ngo, DTM, and Horowitz, JD
- Subjects
Ramipril ,Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Aging ,ACE inhibitors ,Thioredoxin-Interacting Protein ,Blotting, Western ,Regulator ,Myocardial Ischemia ,Angiotensin-Converting Enzyme Inhibitors ,medicine.disease_cause ,Nitric Oxide ,Nitric oxide ,chemistry.chemical_compound ,Young Adult ,nitric oxide ,Internal medicine ,Medicine ,Humans ,Platelet ,Aged ,thioredoxin-interacting protein ,business.industry ,aging ,Middle Aged ,Immunohistochemistry ,Endocrinology ,chemistry ,Guanylate Cyclase ,platelets ,Female ,Cardiology and Cardiovascular Medicine ,business ,Carrier Proteins ,Intracellular ,Oxidative stress ,TXNIP ,medicine.drug ,Follow-Up Studies ,Signal Transduction - 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 nowevaluated the relationship between platelet TXNIP expression and function of the NO/sGC axis in subjects of varying age and during therapy with ramipril. Conclusions: Platelet TXNIP content increaseswith aging, varies inversely with responsiveness to NO, and diminishes rapidly following treatmentwith ramipril. These data suggest that TXNIP-induced oxidative stressmay 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. 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 b 0.05). In the aging subjects there was a significant negative correlation (r = −0.50, p b 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). Refereed/Peer-reviewed
- Published
- 2013