n-3 Polyunsaturated fatty acids alter expression of fibrotic and hypertrophic genes in a dog model of atrial cardiomyopathy

Background

We previously showed that omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The mechanisms underlying this effect are unknown.

Objective

The purpose of this study was to use a genome-wide approach to identify gene expression profiles involved in a new model of AF vulnerability and to determine whether they were altered by PUFA therapy.

Methods

Thirty-six dogs were randomized evenly into three groups. Two groups were paced using simultaneous atrioventricular pacing (SAVP) at 220 bpm for 14 days to induce atrial enlargement, fibrosis, and susceptibility to AF. One group was supplemented with oral PUFAs (850 mg/day) for 21 days, commencing 7 days before the start of pacing (SAVP-PUFAs). The second group received no PUFAs (SAVP-No PUFAs). The remaining dogs were unpaced, unsupplemented controls (CTRL). Atrial tissue was sampled at the end of the protocol. Gene expression was analyzed in four dogs randomly selected from each group (n = 12) via microarray. Results were confirmed with quantitative real-time polymerase chain reaction (RT-PCR) and histology on all 36 dogs.

Results

Microarray or quantitative RT-PCR results showed that SAVP-No PUFAs dogs had significantly increased mRNA levels of protein kinase B (Akt), epidermal growth factor (EGF), JAM3, myosin heavy chain α (MHCα), and CD99 and significantly decreased levels of Smad6 compared with CTRL dogs. Quantitative RT-PCR showed that PUFA supplementation was associated with significant down-regulation of Akt, EGF, JAM3, MHCα, and CD99 levels compared with SAVP-No PUFAs dogs.

Conclusion

The effect of PUFAs on these fibrosis, hypertrophy, and inflammation related genes suggests that, in this model, PUFA-mediated prevention of AF may be due to attenuation of adverse remodeling at the genetic level in response to mechanical stress.

Keywords: Atrial fibrillation, Collagen, Hypertrophy, Omega-3 polyunsaturated fatty acid, Remodeling

Abbreviations: AF, atrial fibrillation, Akt1, protein kinase B, CTRL, control, DHA, docosahexaenoic acid, EGF, epidermal growth factor, EPA, eicosapentaenoic acid, ERK, extracellular signal-related kinase, EST, expression sequence tag, ICD, implantable cardioverter-defibrillator, LAA, left atrial appendage, MAPK, mitogen-activated protein kinase, MHC, myosin heavy chain, MMP, matrix metalloproteinase, PUFA, polyunsaturated fatty acid, RT-PCR, real-time polymerase chain reaction, SAM, significance analysis of microarrays, SAVP, simultaneous atrioventricular pacing, TGF, transforming growth factor, TIMP, tissue inhibitor of metalloproteinase