Focal adhesion kinase mediated signaling on atrial fibrosis in patients with valvular atrial fibrillation_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHANG Peide , LI Fei , QIAO En ,  WANG Wei

Fuwai Hospital, China Academy of Medical Science, National Center for Cardiovascular Disease, Beijing, 100037, P.R.China;

Corresponding author：

WANG Wei, Email: drweiwang0728@hotmail.com

Keywords：

Valvular atrial fibrillation; atrial fibrosis; focal adhesion kinase; signaling pathway

DOI：

10.7507/1007-4848.201807058

Video：

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Objective To explore the changes of focal adhesion kinase (FAK) in the fibrotic atrium of patients with valvular atrial fibrillation and explore its downstream signaling pathways.Methods A total of 45 patients with mitral valve disease were included in this study and were divided into a valvular atrial fibrillation group (VAF, ≥6 months, 25 patients) and a sinus rhythm group (SR, 20 patients) based on having atrial fibrillation or not. The atrial appendage tissue was obtained during the operation , histopathological examination and Western blotting were performed. The degree of atrial fibrosis and changes in FAK and its downstream pathways in fibrotic myocardium were observed.Results This study revealed a higher degree of atrial fibrosis in valvular atrial fibrillation and disordered cell arrangement. Expression of fibroblast differentiation marker alpha smooth muscle actin (α-SMA) was significantly increased in atrial fibrillation, and the expression of FAK and downstream AKT/S6K pathway proteins was up-regulated, while the other signal was observed, there was no significant change in ERK1/2 signaling pathway.Conclusion Atrial fibrosis in valvular atrial fibrillation is an important feature of atrial structural remodeling. We found overproduction of collagen fibers disrupted the continuity of atrial myocytes, leading to abnormal conduction and providing a matrix environment for the development of atrial fibrillation. The expression of focal adhesion kinase and downstream AKT/S6K signaling pathway in fibrotic myocardium may be involved in the process of atrial fibrosis, providing a basis for the study of its mechanism.

Citation： ZHANG Peide, LI Fei, QIAO En, WANG Wei. Focal adhesion kinase mediated signaling on atrial fibrosis in patients with valvular atrial fibrillation. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2019, 26(4): 379-384. doi: 10.7507/1007-4848.201807058 Copy

1.	Friberg L, Rosenqvist M. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace, 2011, 13(5): 626-633.
2.	Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Rev Esp Cardiol (Engl Ed), 2017, 70(1): 50.
3.	Boldt A, Wetzel U, Lauschke J, et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart, 2004, 90(4): 400-405.
4.	Burstein B, Libby E, Calderone A, Nattel S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation, 2008, 117(13): 1630-1641.
5.	Franchini KG. Focal adhesion kinase -- the basis of local hypertrophic signaling domains. J Mol Cell Cardiol, 2012, 52(2): 485-492.
6.	Thannickal VJ, Lee DY, White ES, et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem, 2003, 278(14): 12384-12389.
7.	Lagares D, Kapoor M. Targeting focal adhesion kinase in fibrotic diseases. BioDrugs, 2013, 27(1): 15-23.
8.	Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation, 2008, 118(24): 2498-2505.
9.	Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol, 2008, 51(8): 802-809.
10.	Makati KJ, Alsheikh-Ali AA, Garlitski AC, et al. Advances in mechanisms of atrial fibrillation: structural remodeling, high-frequency fractionated electrograms, and reentrant AF drivers. J Interv Card Electrophysiol, 2008, 23(1): 45-49.
11.	Arold ST. How focal adhesion kinase achieves regulation by linking ligand binding, localization and action. Curr Opin Struct Biol, 2011, 21(6): 808-813.
12.	Akagi T, Murata K, Shishido T, et al. v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras. Mol Cell Biol, 2002, 22(20): 7015-7023.
13.	Turner NA. Therapeutic regulation of cardiac fibroblast function: targeting stress-activated protein kinase pathways. Future Cardiol, 2011, 7(5): 673-691.
14.	Sbroggio M, Bertero A, Velasco S, et al. ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci, 2011, 124(Pt 20): 3515-3524.
15.	Fan GP, Wang W, Zhao H, et al. Pharmacological inhibition of focal adhesion kinase attenuates cardiac fibrosis in mice cardiac fibroblast and post-myocardial-infarction models. Cell Physiol Biochem, 2015, 37(2): 515-526.
16.	Zhang J, Fan G, Zhao H, et al. Targeted inhibition of focal adhesion kinase attenuates cardiac fibrosis and preserves heart function in adverse cardiac remodeling. Sci Rep, 2017, 7: 43146.
17.	Liu S, Xu SW, Kennedy L, et al. FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cel,l, 2007, 18(6): 2169-2178.
18.	Ding Q, Gladson CL, Wu H, et al. Focal adhesion kinase (FAK)-related non-kinase inhibits myofibroblast differentiation through differential MAPK activation in a FAK-dependent manner. J Biol Chem, 2008, 283(40): 26839-6849.

1. Friberg L, Rosenqvist M. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace, 2011, 13(5): 626-633.
2. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Rev Esp Cardiol (Engl Ed), 2017, 70(1): 50.
3. Boldt A, Wetzel U, Lauschke J, et al. Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart, 2004, 90(4): 400-405.
4. Burstein B, Libby E, Calderone A, Nattel S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation, 2008, 117(13): 1630-1641.
5. Franchini KG. Focal adhesion kinase -- the basis of local hypertrophic signaling domains. J Mol Cell Cardiol, 2012, 52(2): 485-492.
6. Thannickal VJ, Lee DY, White ES, et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem, 2003, 278(14): 12384-12389.
7. Lagares D, Kapoor M. Targeting focal adhesion kinase in fibrotic diseases. BioDrugs, 2013, 27(1): 15-23.
8. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation, 2008, 118(24): 2498-2505.
9. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol, 2008, 51(8): 802-809.
10. Makati KJ, Alsheikh-Ali AA, Garlitski AC, et al. Advances in mechanisms of atrial fibrillation: structural remodeling, high-frequency fractionated electrograms, and reentrant AF drivers. J Interv Card Electrophysiol, 2008, 23(1): 45-49.
11. Arold ST. How focal adhesion kinase achieves regulation by linking ligand binding, localization and action. Curr Opin Struct Biol, 2011, 21(6): 808-813.
12. Akagi T, Murata K, Shishido T, et al. v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras. Mol Cell Biol, 2002, 22(20): 7015-7023.
13. Turner NA. Therapeutic regulation of cardiac fibroblast function: targeting stress-activated protein kinase pathways. Future Cardiol, 2011, 7(5): 673-691.
14. Sbroggio M, Bertero A, Velasco S, et al. ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci, 2011, 124(Pt 20): 3515-3524.
15. Fan GP, Wang W, Zhao H, et al. Pharmacological inhibition of focal adhesion kinase attenuates cardiac fibrosis in mice cardiac fibroblast and post-myocardial-infarction models. Cell Physiol Biochem, 2015, 37(2): 515-526.
16. Zhang J, Fan G, Zhao H, et al. Targeted inhibition of focal adhesion kinase attenuates cardiac fibrosis and preserves heart function in adverse cardiac remodeling. Sci Rep, 2017, 7: 43146.
17. Liu S, Xu SW, Kennedy L, et al. FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cel,l, 2007, 18(6): 2169-2178.
18. Ding Q, Gladson CL, Wu H, et al. Focal adhesion kinase (FAK)-related non-kinase inhibits myofibroblast differentiation through differential MAPK activation in a FAK-dependent manner. J Biol Chem, 2008, 283(40): 26839-6849.

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Focal adhesion kinase mediated signaling on atrial fibrosis in patients with valvular atrial fibrillation

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