title: Reciprocal regulation of NO signaling and TXNIP expression in humans: impact of aging and ramipril therapy.
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.
  
  
  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: Cardiology Unit, Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia.
authors: Aaron L
authors: AL
authors: Sverdlov
authors: Wai P A
authors: WP
authors: Chan
authors: Nathan E K
authors: NE
authors: Procter
authors: Yuliy Y
authors: YY
authors: Chirkov
authors: Doan T M
authors: DT
authors: Ngo
authors: John D
authors: JD
authors: Horowitz
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000097:blood*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006162:Guanylate Cyclase / Q000097:blood / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000188:drug therapy; D009569:Nitric Oxide / Q000097:blood*; D017257:Ramipril / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; C486715:TXNIP protein, human; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D017257:Ramipril
keywords: ACE inhibitors; Aging; Nitric oxide; Platelets; Thioredoxin-interacting protein