Thioredoxin-1 attenuates atrial remodeling in pressure-overload heart failure by inhibiting SP1/TGF-beta/Smad signal

Oxidative stress is a core pathological hallmark of pressure-overload heart failure (HF), and thioredoxin-1 (Trx1) exerts critical cytoprotective effects against oxidative injury. Here, we hypothesized that Trx1 downregulation in atrial fibroblasts contributes to elevated atrial fibrillation (AF) susceptibility in the setting of pressure-overload HF.

To investigate Trx1's gain-of-function effects on atrial remodeling, we developed adeno-associated virus 9 (AAV9)-mediated atrial-specific Trx1-overexpressing mice. These mice underwent transverse aortic constriction (TAC) to induce pressure overload. Cardiac function and atrial fibroblasts were evaluated in both groups post-TAC. Conversely, Trx1 knockdown was performed to assess loss-of-function effects. Atrial tissue proteomic sequencing explored the underlying molecular mechanisms.

Bioinformatic analysis revealed significant Trx1 downregulation in cardiac tissues from patients with pressure-overload HF. In TAC mice, atrial Trx1 expression was markedly reduced, predominantly in atrial fibroblasts. Atrial-specific Trx1 overexpression in TAC-induced mice ameliorated HF phenotypes, attenuated atrial dilation, reduced atrial fibrosis by 15%, decreased AF incidence by 15%, and shortened AF episode duration by 80% versus empty vector controls. Conversely, atrial-specific Trx1 knockdown in TAC mice exacerbated HF, atrial dilation, and fibrosis (90% increase), with 17% higher AF incidence and doubled AF duration. Mechanistically, proteomic and validation assays revealed that Trx1 deficiency relieved its inhibitory effect on specificity protein 1 (SP1); upregulated SP1 enhanced TGF-β1 transcription and Smad family protein binding, thereby activating atrial fibroblasts and driving pathological atrial fibrosis.

Trx1 alleviates pressure-overload TAC-induced atrial structural remodeling and reduces AF susceptibility via suppressing SP1 expression and inhibiting the TGF-β/Smad signaling cascade.