Homocysteine alters Redox Regulation through Thioredoxin‐Interacting Protein: A Novel role of Forkhead Transcription Factor (FOXO‐3a/FKHR‐L1)

The cellular redox balance by pro‐oxidative and anti‐oxidative system plays an important role in Hcy‐induced cardiovascular complications; however the mechanism of such regulation is incompletely defined. Thiredoxin (Trx) and the glutathione are the thiol‐reducing systems that maintain a reduced intracellular state. A thioredoxin‐interacting protein (Txnip) binds with Trx and inhibits its ability to reduce sulphydryl groups via NADPH oxidation. FOXO subfamily of forkhead transcription factor is downstream of phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt) signaling pathway. Recent studies have identified TXNIP as a potential FOXO (forkhead transcription factor) target. We hypothesize, Hcy induces the oxidative stress by augmenting the FKHR‐L1 (FOXO‐3a)‐mediated transcription of TXNIP via PI3K/Akt signaling pathway. We found that Akt/FKHR‐L1 (FOXO‐3a) signaling axis is functional and FKHR‐L1 is downstream target of Akt in rat heart microvascular endothelial cells. Hcy dephosphorylates Akt and FKHR‐L1 (FOXO‐3a). These effects were PI3K‐dependent. Hcy‐mediated dephosphorylation of FKHR‐L1 abrogates the transcription of TXNIP and expression of Txnip resulting in down regulation of Trx anti‐oxidant system. Taken together our data suggest that Hcy altered the redox state in MVEC by modulating the regulation of Txip by Akt/FKHR‐L1 (FOXO‐3a) signaling axis.