Induction of Sirt1 and PGC1α Signalling Pathway in Cardiac Mitochondrial Biogenesis by Aspirin

Abstract

Aims: We hypothesized that acetyl salicylic acid (Aspirin, ASA) treament has ability to induce Sirtuin 1, 4 (Sirt1 and Sirt4) and it downstream targets, peroxisome proliferatoractivated receptor-gamma co-activator-1α (PGC1α) and mitochondrial transcription factor A (Tfam) gene in cultured HL1 cardiomyocytes. We also assume that hydrogen peroxide (H 2 O 2 ) formed during redox reactions is inducer of Sirt1 gene. Methods and Results:Atrial Cardiomyocyts HL1 cells were cultured in Claycomb medium with 10% FBS, 100μmol/L norepinephrine, and 4 mmol/L L-glutamine (Invitrogen, Carlsbad, CA) in gelatin coated flasks. Cells were maintained at 37°C in an atmosphere containing 5% CO 2 . Cells were then incubated with either 50 μM and 0.25 mM ASA for 48 h in the same medium. Respective controls were maintained with alcohol alone. At the end of the treatment, the medium was removed and the cells were washed with PBS and harvested in Trizol® for isolation of RNA. RT-PCR was performed for the analysis of gene expression. Our results in cultured HL1 cardiomyocytes showed ASA treament induced Sirt1 and Sirt4 genes via H 2 O 2 generation. Increase in Sirt1 gene activated PGC1α and Tfam gene. ASA have also induced antioxidant enzymes, glutathione peroxidase (GPX) and catalase (CAT) gene. Conclusion:We conclude from our results that ASA is a potential anti-atherosclerotic drug and an increase in Sirt1 gene further suggest that it can induce anti-inflammatory action. It can also interfere with Nfkb signaling pathway that can prevent foam cell formation. However, specific overexpression of PGC1α and Tfam gene in HL1 cardiomyocyte can increase mitochondrial biogenesis and prevent the development of heart failure.