Regulation of calcium pump through Notch/Jagged/Hes signaling pathway in canine model of chronic atrial fibrillation.

OBJECTIVE

Using a canine model of atrial fibrillation (AF) induced by chronic pacing of left atrial fibrillation, the present study aimed to investigate the protein expression and content change of Notch-1 and its downstream target genes including Hes1, Jagged1, and SERCA2a in the atrial myocardium of canines with chronic AF. Furthermore, the correlation between Notch-1/Hes1/Jagged1 and the SERCA2a calcium pump was also analyzed.

METHODS

Ten healthy Beagle dogs including both males and females, aged 7-9 years were randomly divided into a sham group (n = 5) and AF group (n = 5). The AF group underwent minimally invasive surgery with implantation of a pacemaker into the left atrial appendage for induction of AF. After 8 weeks of pacemaker implantation, animals were euthanized and specimens from the right and left atrial free walls were excised for histologic and biochemical analyses.

RESULTS

After 8 weeks' pacemaker implantation, immunohistochemical expression of Notch-1, Hes1, Jagget1 and SERCA2a in the sham group was positive. Compared with the sham operation group, the intensity of Notch-1, Hes1 and Jagget1 in AF group was stronger with a significant increasing trend in the intensity of the color, respectively. The expression of SERCA2a was weak; the intensity decreased significantly (P < 0.05). Pearson correlation analysis revealed that in the AF group, Notch-1 was negatively correlated with SERCA2a (r = -0.77, P = 0.028), and was positively correlated with Hes1 and Jagged1 (r = 0.92, P = 0.014; r = 0.73, P = 0.030) proteins, respectively.

CONCLUSION

The activation of the Notch signaling pathway was associated with a decrease in SERCA2a protein expression and contributes to the development and maintenance of electrical remodeling in AF through modulation of calcium pump function and calcium homeostasis.