The (CCTTT)N Repeat Polymorphism in the Promoter of iNOS Gene and the Risk of Atrial Fibrillation

Atrial fibrillation (AF) is now recognized to be the most common sustained cardiac arrhythmia and a major public health burden. By genetic association study, some genetic variants or polymorphisms related to the mechanism of AF have been found to be associated with common AF. Accumulating evidence suggests that there is a link between oxidative processes and AF. An altered nitric oxide (NO)–redox balance in the atrial myocardium may be implicated in the pathogenesis of AF and AF-induced atrial remodeling. Recently it was shown that NO overproduction derived from inducible nitric oxide synthase (iNOS) increases cardiomyocyte apoptosis in human permanent AF. We hypothesize that the (CCTTT)n pentanucleotide repeat polymorphism in the promoter region of iNOS gene is associated with AF by modifying atrial remodeling response to oxidative stress. Therefore, we plan to investigate whether: 1. The (CCTTT)n repeats polymorphism in the promoter region of iNOS gene is associated with the risk of atrial fibrillation. 2. The (CCTTT)n repeats polymorphism could functionally determine the iNOS expression in AF tissues. 3. Rapid activation of HL-1 atrial myocytes induces the expression of iNOS. 4. The induction of iNOS in HL-1 atrial myocytes by rapid pacing is at transcriptional level and is determined by the length (number) of pentanucleotide (CCTTT) repeats in the promoter region of iNOS gene. 5. iNOS plays an important role on rapid pacing-induced oxidative stress in HL-1 atrial myocytes. 6. iNOS plays an important role on rapid pacing-induced electrical and structural remodeling in HL-1 atrial myocytes. Hopefully, our study will offer a deeper understanding about oxidative stress-induced cellular structural and electrical remodeling in AF. The results of our study may help define the role of iNOS in AF and provide a useful target for therapeutic intervention in AF.

Project ID:PC10207-0832
External Project ID:NSC102-2314-B182-034