Abstract 044: Transient Receptor Potential Channel 6 (TRPC6) Is An Important Mediator Of Mechanical Stretch Responses In The Atrial Endocardial Endothelium.

Abstract

Atrial fibrillation (AF) is the most common heart arrhythmia and a major risk factor for thromboembolic stroke and hearth failure. Atrial pressure and/or volume overload that cause increased mechanical stretch in the atrium are the common features of the diseases that cause AF. The latter suggests that mechanical stress has a major role in the pathogenesis of AF. The atrial endocardial endothelium (AE) is the interface between the myocardium and the circulating blood but its role in the mechanotransduction in the atrium is unknown. Endothelial cells (EC) are very sensitive and responsive to external mechanical stimuli and AE dysfunction has been reported in individuals with AF. We therefore hypothesized that the AE is an important mediator of stretch responses in the atrium and that stretch-induced AE dysfunction may be critical for initiation and/or maintenance of AF. We investigated the AE responses to increased mechanical stress by subjecting novel primary AE cells to mechanical stretch. The mechanical stretch conditions included cyclic stretch of 30 cycles/min at 10 percent displacement. The AE cells were stretched for 1-10 min, and 1, 4, 8, and 24h. Changes in the cell shape with elongation, hypertrophy and re-alignment of the cells and their stress fibres in a direction perpendicular to the lines of stretch were first observed after 1h of stretch. TRPC6 is a stretch sensitive ion channel and important regulator of Ca2+-signalling in the EC cells. Immunostaining and Western blot analysis showed redistribution and changed levels of expression of TRPC6 in the stretched AE cells, respectively. The latter suggested changed TRPC6 activity which was evaluated by measuring extracellular Ca2+ influx through the TRPC6 channels in the AE cells under baseline and stretch conditions. We found that short-stretch (1-10min) increased TRPC6 activity, while the long stretch (1-24h) silenced it. Based on these findings it could be concluded that TRPC6 is an important mediator of the mechanical stretch responses in the AE; the functional consequences of the altered channel activity are predetermined by the duration of the stretch-stimulus; and TRPC6 changes in the stretched AE may cause AE dysfunction through altered Ca2+ signalling that contributes to AF development.