Abstract
Epidemiological studies have shown a strong correlation between tumor and AF. However, the molecular link between tumor and AF remains unknown. ECRG4, a tumor suppressor gene that is expressed in the A-V node and in sporadic ventricular myocytes, inhibits tumorigenesis and monitors tissue homeostasis by functioning as a ‘sentinel’ molecule gauging inflammatory and cell proliferative responses. To explore the potential physiological function of Ecrg4 in heart, we evaluated its distribution in heart, analyzed its expression in patients with persistent AF and in a canine AF model, and dissected the molecular events downstream of Ecrg4. The results showed that the level of Ecrg4 expression is homogenously high in atria and the conduction systems and in sporadic ventricular myocytes. Importantly, the expression of Ecrg4 was significantly decreased in atrial appendages of AF patients than patients with SR. Moreover, in rapid pacing canine AF models, the expression of ECRG4 in atria was significantly decreased compared to that of the controls. Mechanistically, knockdown ECRG4 in atrial myocytes significantly shortened the APDs, inhibited the expression of Gja1, and activated pro-inflammatory cascades and genes involved in cardiac remodeling. These results suggest that Ecrg4 may play a critical role in the pathogenesis of AF.
Highlights
Significant progress has been achieved in the management of AF, the pathogenesis of AF remains incompletely understood
When the expression of ECRG4 was evaluated by real-time PCR (n = 9) (Fig. 2), Sinus node (SN) and left atria
1), knockdown ECRG4 significantly up-regulated the expression of proinflammatory genes IL1a, IL6, monocyte chemoattractant protein-1 (MCP1) (P < 0.05 in all) but not that of NF-kb p50 (Fig. 7A), down-regulated Gap junction alpha-1 protein (Gja1) (P < 0.05), and up-regulated MMP3, s100a1 and s100a8 (Fig. 7B) (P < 0.05 in all). These results suggest that Ecrg[4] may play a critical role in the pathogenesis of AF, and loss of Ecrg[4] may initiate the cascades of atrial remodeling
Summary
Significant progress has been achieved in the management of AF, the pathogenesis of AF remains incompletely understood. The coverslips were used for patch-clamping to record action potential (AP) and the cells on the edge of the wells were used to confirm the knockdown of ECRG4 and to evaluate the expression of genes commonly involved in inflammation and atria remodeling by real-time PCR.
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