Effect of left atrial enlargement on expression of the angiotensinⅡ, signal transducers and activators of transcription 3 and Rac GTPase activating protein 1 signaling pathways in patients with persistent atrial fibrillation and rheumatic heart disease_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LAN Huai ¹ ,  WANG Huishan ¹ , XUE Xiaodong ¹ , YIN Zongtao ¹ , ZHU Yan ¹ , HAN Jinsong ¹ , MA Dongchu ² , PU Feifei ²

1. Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, 110016, P.R.China;
2. Department of Experimental Medicine, General Hospital of Shenyang Military Area Command, Shenyang, 110016, P.R.China;

Corresponding author：

WANG Huishan, Email: huishanwangcc@163.com

Keywords：

Atrial fibrillation; rheumatic heart disease; angiotensinⅡ; Rac GTPase activating protein 1; signal transducers and activators of transcription 3

DOI：

10.7507/1007-4848.201710021

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Objective To evaluate the effect of left atrial enlargement on atrial myocardial fibrosis degree and levels of the angiotensinⅡ (AngⅡ)/Rac GTPase activating protein 1 (Rac1)/signal transducersand activators of transcription 3 (STAT3) signaling pathways expressing in patients with persistent atrial fibrillation and rheumatic heart disease (RHD). Methods From March to December 2011, 30 patients with RHD who underwent prosthetic valve replacement in our hospital were enrolled, including 16 males and 14 females, aged 42-70 (56.9±6.8) years. Twenty RHD patients with persistent atrial fibrillation as a research group and ten RHD patients with sinus rhythm as a control group (group A) underwent transthoracic echocardiography and right atrial appendage (RAA) tissue samples were obtained from these patients during mitral/aortic valve replacement operation. The research group according to left atrial diameter (LAD) was divided into two groups, ten patients in each group: a group B with LAD of 50–65 mm and a group C with LAD of LAD>65 mm. For each sample, histological examination was performed by hematoxylin-eosin and Masson’s trichrome staining. Light-microscopic pictures of atrial tissues samples were stained and tissue fibrosis degree in each group was analyzed. AngⅡ concentration was measured by enzyme linked immunosorbent assay. Rac1 and STAT3 were measured by western blotting. Results LAD was significantly greater in AF patients with RHD than in the control group. Hematoxylin-eosin staining demonstrated highly organized arrangement of atrial muscles in the control group and significant derangement in both group B and group C with reduced cell density and increased cell size. Moreover, Masson’s trichrome staining showed that atrial myocytes were surrounded by large trunks of collagen fibers in both group B and group C, but not in the group A. There was a positive correlation between atrial tissue fibrosis and LAD. AngⅡ content was positively correlated with LAD. Similarly, Rac1 and STAT3 protein levels were found considerably higher in the group C and group B than in the group A with excellent correlation to LAD. Conclusion In patients with RHD complicated with persistent atrial fibrillation, the degree of atrial fibrosis and the expression level of AngⅡ/Rac1/STAT3 signaling pathways significantly increase with the left atrialenlargement.

Citation： LAN Huai, WANG Huishan, XUE Xiaodong, YIN Zongtao, ZHU Yan, HAN Jinsong, MA Dongchu, PU Feifei. Effect of left atrial enlargement on expression of the angiotensinⅡ, signal transducers and activators of transcription 3 and Rac GTPase activating protein 1 signaling pathways in patients with persistent atrial fibrillation and rheumatic heart disease. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2018, 25(11): 993-999. doi: 10.7507/1007-4848.201710021 Copy

1.	Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation, 1998, 98(10): 946-952.
2.	Diker E, Aydogdu S, Ozdemir M, et al. Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. Am J Cardiol, 1996, 77(1): 96-98.
3.	Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in two canine models of atrial fibrillation. Circ Res, 2007, 100(3): 425-433.
4.	Everett TH 4th, Li H, Mangrum JM, et al. Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation. Circulation, 2000, 102(12): 1454-1460.
5.	Li D, Shinagawa K, Pang L, et al. Effects of angiotensin eonveing enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation, 2001, 104(21): 2608-2614.
6.	Nazir SA, Lab MJ. Mechanoelectric feedback in the atrium of the isolated guinea-pig heart. Cardiovasc Res, 1996, 32(1): 112-119.
7.	Tsai CT, Lai LP, Kuo KT, et al. Angiotensin Ⅱ activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation, 2008, 117(3): 344-355.
8.	Spach MS. Mounting evidence that fibrosis generates a major mechanism for atrial fibrillation. Circ Res, 2007, 101(8): 743-745.
9.	Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J, 2006, 27(5): 512-518.
10.	Dostal DE, Hunt RA, Kule CE, et al. Molecular mechanisms of angiotensin Ⅱ in modulating cardiac function: intracardiac effects and signal transduction pathways. J Mol Cell Cardiol, 1997, 29(11): 2893-2902.
11.	Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal, 1997, 9(5): 337-351.
12.	Ushio-Fukai M, Alexander RW, Akers M, et al. p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin Ⅱ. Role in vascular smooth muscle cell hypertrophy. J Biol Chem, 1998, 273(24): 15022-15029.
13.	Zou Y, Komuro I, Yamazaki T, et al. Cell type-specific angiotensin Ⅱ-evoked signal transduction pathways: critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res, 1998, 82(3): 337-345.
14.	Adam O, Lavall D, Theobald K, et al. Rac1-induced connective tissue growth factor regulates connexin 43 and N-cadherin expression in atrial fibrillation. J Am Coll Cardiol, 2010, 55(5): 469-480.
15.	Abo A, Pick E, Hall A, et al. Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature, 1991, 353(6345): 668-670.
16.	Adam O, Frost G, Custodis F, et al. Role of Rac1 GTPase activation in atrial fibrillation. J Am Coll Cardiol, 2007, 50(4): 359-367.
17.	Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation, 2005, 112(9): 1266-1273.
18.	Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest, 2001, 108(10): 1429-1437.
19.	Adam O, Neuberger HR, Böhm M, et al. Prevention of atrial fibrillation with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Circulation, 2008, 118(12): 1285-1293.
20.	McGaffin KR, Zou B, McTiernan CF, et al. Leptin attenuates cardiac apoptosis after chronic ischaemic injury. Cardiovasc Res, 2009, 83(2): 313-324.
21.	Paradis P, Dali-Youcef N, Paradis FW, et al. Overexpression of angiotensin Ⅱ type Ⅰ receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A, 2000, 97(2): 931-936.
22.	Yue H, Li W, Desnoyer R, et al. Role of nuclear unphosphorylated STAT3 in angiotensin Ⅱ type 1 receptor-induced cardiac hypertrophy. Cardiovasc Res, 2010, 85(1): 90-99.

1. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation, 1998, 98(10): 946-952.
2. Diker E, Aydogdu S, Ozdemir M, et al. Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. Am J Cardiol, 1996, 77(1): 96-98.
3. Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in two canine models of atrial fibrillation. Circ Res, 2007, 100(3): 425-433.
4. Everett TH 4th, Li H, Mangrum JM, et al. Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation. Circulation, 2000, 102(12): 1454-1460.
5. Li D, Shinagawa K, Pang L, et al. Effects of angiotensin eonveing enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation, 2001, 104(21): 2608-2614.
6. Nazir SA, Lab MJ. Mechanoelectric feedback in the atrium of the isolated guinea-pig heart. Cardiovasc Res, 1996, 32(1): 112-119.
7. Tsai CT, Lai LP, Kuo KT, et al. Angiotensin Ⅱ activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation, 2008, 117(3): 344-355.
8. Spach MS. Mounting evidence that fibrosis generates a major mechanism for atrial fibrillation. Circ Res, 2007, 101(8): 743-745.
9. Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J, 2006, 27(5): 512-518.
10. Dostal DE, Hunt RA, Kule CE, et al. Molecular mechanisms of angiotensin Ⅱ in modulating cardiac function: intracardiac effects and signal transduction pathways. J Mol Cell Cardiol, 1997, 29(11): 2893-2902.
11. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal, 1997, 9(5): 337-351.
12. Ushio-Fukai M, Alexander RW, Akers M, et al. p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin Ⅱ. Role in vascular smooth muscle cell hypertrophy. J Biol Chem, 1998, 273(24): 15022-15029.
13. Zou Y, Komuro I, Yamazaki T, et al. Cell type-specific angiotensin Ⅱ-evoked signal transduction pathways: critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res, 1998, 82(3): 337-345.
14. Adam O, Lavall D, Theobald K, et al. Rac1-induced connective tissue growth factor regulates connexin 43 and N-cadherin expression in atrial fibrillation. J Am Coll Cardiol, 2010, 55(5): 469-480.
15. Abo A, Pick E, Hall A, et al. Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature, 1991, 353(6345): 668-670.
16. Adam O, Frost G, Custodis F, et al. Role of Rac1 GTPase activation in atrial fibrillation. J Am Coll Cardiol, 2007, 50(4): 359-367.
17. Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation, 2005, 112(9): 1266-1273.
18. Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest, 2001, 108(10): 1429-1437.
19. Adam O, Neuberger HR, Böhm M, et al. Prevention of atrial fibrillation with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Circulation, 2008, 118(12): 1285-1293.
20. McGaffin KR, Zou B, McTiernan CF, et al. Leptin attenuates cardiac apoptosis after chronic ischaemic injury. Cardiovasc Res, 2009, 83(2): 313-324.
21. Paradis P, Dali-Youcef N, Paradis FW, et al. Overexpression of angiotensin Ⅱ type Ⅰ receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A, 2000, 97(2): 931-936.
22. Yue H, Li W, Desnoyer R, et al. Role of nuclear unphosphorylated STAT3 in angiotensin Ⅱ type 1 receptor-induced cardiac hypertrophy. Cardiovasc Res, 2010, 85(1): 90-99.

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Effect of left atrial enlargement on expression of the angiotensinⅡ, signal transducers and activators of transcription 3 and Rac GTPase activating protein 1 signaling pathways in patients with persistent atrial fibrillation and rheumatic heart disease

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