Abstract 1518: Angiotensin II Leads to Structural Remodeling in Atrial Fibrillation via Activation of Rac1 and Connective Tissue Growth Factor
Backround: The molecular signalling of the atrial structural remodelling during the pathogenesis of atrial fibrillation (AF) is only partially understood.
Methods and Results: Matched samples of left atrium from patients with AF were subjected to Affymetrix expression analysis which showed marked upregulation of connective tissue growth factor (CTGF) compared to patients in sinus rhythm (SR). Western Blot analysis confirmed upregulation of CTGF expression (205±68%, n=6). This was associated with increased fibrosis, a 3-fold higher activity of Rac1-GTPase (362±98%, PAK pull-down assays), a 2-fold upregulation of N-cadherin (196±54%) and elevated protein expression of connexin 43 (Cx43, 188±18%). ELISA showed 8-fold elevated Angiotensin II tissue levels in AF (28 pg/mg protein in AF vs. 4 pg/mg protein in SR). In primary neonatal rat cardiac myocytes und fibrocytes, the specific small molecule inhibitor of Rac1, NSC23766 or simvastatin completely prevented angiotensin II induced upregulation of CTGF, Cx43 and N-cadherin expression. The importance of Rac1 GTPase for structural remodeling in vivo was studied in transgenic mice with cardiac overexpression (αMHC promoter) of Rac1 (RacET) who develope AF at old age. Compared to wildtype, left atria of RacET mice showed an elevation of CTGF (368±28%), Cx43 (317±68%) and N-cadherin (752±54%) protein expression. Inhibition of Rac1 activity by statin treatment prevented these effects. All effects are significant with p<0.05.
Conclusion: Left atria of patients with AF are characterized by upregulation of angiotensin II tissue concentrations, Rac1 activity and increased expression of CTGF. Angiotensin II and Rac1 mediated upregulation of CTGF, Cx43 and N-cadherin can be prevented by statins in cultured cardiac cells and in mice. Rac1 may therefore represent a target for the prevention of structural remodeling in atrial fibrillation.