Abstract 1227: Thioredoxin1 Upregulates PGC-1α and NRF1 and Enhances Mitochondrial Functions
Thioredoxin1 (Trx1) is an anti-oxidant that inhibits cardiac hypertrophy and protects the heart from pathological insults, such as ischemia/reperfusion. To further elucidate the cardiac role of Trx1, we employed cDNA microarray analyses using hearts from transgenic mice with cardiac specific overexpression of Trx1 (Tg-Trx1, n=4) and non-transgenic mice (NTg, n=4). Unexpectedly, the pathway analysis identified that genes involved in the TCA cycle and oxidative phosphorylation are collectively upregulated in Tg-Trx1. A transcription factor binding site analysis also indicated that upregulated genes frequently contain binding sites for nuclear respiratory factor 1 (NRF1) and cAMP response element binding protein (CREB), a major transcription factor for peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Consistently, PGC-1α, a key regulator of mitochondriagenesis, was among the significantly upregulated genes in Tg-Trx1. Protein expression of NRF1 and PGC-1α was increased in Tg-Trx1 (132% and 155%, p<0.05). Transcriptional activity of NRF1 was enhanced in Trx1-overexpressing myocytes (154%, p<0.01). Furthermore, upregulation of mitochondrial genes, including cytochrome c oxidase (COX) components (cytochrome c 122%, COXIV 126%, and COXVb 156%, p<0.05), was confirmed at protein levels in Tg-Trx1. Activity of mitochondrial enzymes, such as citrate synthase (125%, p<0.05) and COX (116%, p<0.05), and the cardiac ATP content (141%, p<0.05) were significantly higher in Tg-Trx1. In addition, expression of mitochondrial transcription factor A, a NRF1 target and a transcription and replication factor for mitochondria, was significantly upregulated (164%, p<0.05). Concomitantly, the ratio of mitochondrial DNA vs genomic DNA was increased in Tg-Trx1 (127%, p<0.05). Finally, Trx1 partially reversed cardiac dysfunction in transgenic mice with cardiac specific overexpression of mammalian sterile 20 like kinase 1, which are known to have mitochondrial dysfunction in vivo (+17% in LV ejection fraction). These results suggest that Trx1 upregulates mitochondrial proteins through PGC-1α and NRF1, thereby enhancing mitochondrial functions in cardiac myocytes, which may in part explain cardioprotective effects of Trx1.