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.
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.
Authors: Chukwudiebube N Ajaero; Nathan E K Procter; Yuliy Y Chirkov; Tamila Heresztyn; Margaret A Arstall; Andrew D McGavigan; Michael P Frenneaux; John D Horowitz Journal: Heart Vessels Date: 2019-08-27 Impact factor: 2.037
Authors: Nathan Ek Procter; Jocasta Ball; Tamila Heresztyn; Vivek B Nooney; Saifei Liu; Cher-Rin Chong; Doan Tm Ngo; Jeffrey S Isenberg; Yuliy Y Chirkov; Simon Stewart; John D Horowitz Journal: Am J Cardiovasc Dis Date: 2015-08-01
Authors: Aaron L Sverdlov; Doan T M Ngo; Wai P A Chan; Yuliy Y Chirkov; John D Horowitz Journal: J Am Heart Assoc Date: 2014-08-18 Impact factor: 5.501
Authors: Nathan Ek Procter; Jocasta Ball; Doan Tm Ngo; Jeffrey S Isenberg; Elaine M Hylek; Yuliy Y Chirkov; Simon Stewart; John D Horowitz Journal: J Geriatr Cardiol Date: 2016-03 Impact factor: 3.327