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研究生(外文):Yen-Yu Lu
論文名稱(外文):Role of collagen-integrin interaction in electrical remodeling of atrial and pulmonary vein cardiomyocytes during cardiac fibrosis
中文關鍵詞:纖維化,細胞外間質,電生理,鈣離子恆定,膠原蛋白,肺靜脈,心房顫動p38 MAPK
外文關鍵詞:Fibrosisextracellular matrixelectrophysiologycalcium homeostasis CollagenPulmonary veinsAtrial fibrillationp38 MAPK
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結果:與對照組相比,膠原蛋白處理之HL-1心肌細胞表現出較大的細胞內鈣離子濃度和較大的肌漿網內鈣含量,膠原蛋白處理之HL-1心肌亦有較高SERCA2a蛋白和Thr17磷酸化phospholamban的表現,但Na+/Ca2+exchanger and ryanodine receptor的表現並無差異。膠原蛋白處理HL-1心肌細胞有較大的動作電位及較短的90%動作電位的持續時間。此外,膠原蛋白處理之HL -1細胞有較大的Ito和IKsus值。Losartan則會減少膠原蛋白所造成細胞內鈣離子, 動作電位形態,離子電流, SERCA2a以及Thr17磷酸化phospholamban表現的變化。在研究II中,膠原蛋白處理的肺靜脈心肌細胞跳動較快及較大的delayed afterdepolarization。此外,膠原蛋白處理的肺靜脈心肌細胞表現出較大的Ito,small-conductance Ca2 +-activated K+ current,inward rectifier potassium current,pacemaker current,late sodium current,但sodium current,IKsus和L-type calcium current是相似的。膠原蛋白增加肺靜脈心肌細胞p38 MAPK磷酸化, SB203580 ( p38 MAPK的催化活性抑製劑)則明顯減少膠原蛋白對肺靜脈心肌細胞自動性和動作電位的變化。
結論:這兩項研究表明,膠原蛋白可以透過腎素-血管收縮素系統來直接調節心房心肌細胞的鈣離子動力學和影響心電生理。這些研究結果表明膠原蛋白在纖維化過程中對心臟電生理的重塑起著重要的作用。此外,膠原蛋白可以通過活化p38 MAPK直接增加肺靜脈心肌細胞心律失常,這可能有助於了解心房顫動的發病機制。
Background: Myocardial fibrosis plays a critical role in heart failure, resulting in cardiac structural and electrical remodeling which can induce atrial arrhythmias. Atrial fibrillation (AF) is the most common sustained arrhythmia. Pulmonary veins (PVs) are important foci for AF genesis. Cardiac fibrosis with enhanced extracellular collagen plays a critical role in the pathophysiology of AF through structural and electrical remodeling. However, it is not clear whether collagen can directly regulate the calcium homeostasis and the electrophysiologic characteristics of cardiomyocytes. The aim of our study was to determine the effects of collagen on calcium homeostasis and the electrical properties of atrial and pulmonary cardiomyocytes.
Methods: In study I, HL-1 cardiomyocytes were cultured with and without collagen type I (1 or 10 μg/mL) or losartan (10 μmol/L). Whole-cell clamp, indo-1 fluorescence, and Western blotting were used to evaluate the action potential (AP) and ionic currents, intracellular calcium homeostasis, and calcium regulatory proteins. In study II, APs and ionic currents were investigated in isolated male New Zealand rabbit PV cardiomyocytes with and without collagen incubation (10 μg/ml, 5–7 h) using the whole-cell patch-clamp technique.
Results In study I, collagen (10 μg/mL)–treated HL-1 cardiomyocytes exhibited larger intracellular calcium ([Ca2+]i) transients and a larger sarcoplasmic reticulum (SR) calcium content compared with the control samples,. Collagen–treated HL-1 cardiomyocytes had higher expression of SR ATPase (SERCA2a) and Thr17-phosphorylated phospholamban but similar protein expressions of the Na+/Ca2+exchanger and ryanodine receptor. Collagen–treated HL-1 cardiomyocytes had larger AP amplitude and shorter 90% of AP duration than control cells. Moreover, collagen–treated HL-1 cells had larger Ito and IKsus values than control cells. The administration of losartan (10 μmol/L) attenuated collagen-induced changes in [Ca2+]i transients, [Ca2+]i stores, AP morphology, ionic currents, SERCA2a, and Thr17-phosphorylated phospholamban expressions.
In study II, collagen-treated PV cardiomyocytes had a faster beating rate and a larger amplitude of delayed afterdepolarization as compared to control PV cardiomyocytes. Moreover, collagen-treated PV cardiomyocytes showed a larger transient outward potassium current, small-conductance Ca2 +-activated K+ current, inward rectifier potassium current, pacemaker current, and late sodium current than control PV cardiomyocytes, but amplitudes of the sodium current, sustained outward potassium current, and L-type calcium current were similar. Collagen increased the p38 MAPK phosphorylation in PV cardiomyocytes as compared to control. The change of the spontaneous activity and action potential morphology were ameliorated by SB203580 (the p38 MAPK catalytic activity inhibitor).
Conclusions: These two studies demonstrate that collagen can directly modulate the calcium dynamics and electrical activities of atrial cardiomyocytes, which are associated with the renin-angiotensin system. These findings suggest a critical role of collagen in electrical remodeling during fibrosis. Besides, collagen can directly increase PV cardiomyocyte arrhythmogenesis through p38 MAPK activation, which may contribute to the pathogenesis of AF.
List of Publications i
Abbreviations ii
Abstract in Chinese iii
Abstract in English iv
1. Introduction
1.1 Pathogenesis of Myocardial Fibrosis and the Relationship with Extracellular Matrix 1~2
1.2 Myocardial Fibrosis and Atrial Arrhythmias 2~3
1.3 Myocardial Fibrosis and Calcium Homeostasis 3~4
1.4 The Role of ECM in Regulation of Signaling Pathway 4~5
1.5 Aims of the Thesis 5~6
2. Materials and Methods
2.1 Cell Culture 6
2.2 Isolation of PV cardiomyocytes 6~7
2.3 Measurement of Calcium Transients and Intracellular Calcium 7~8
2.4 Western Blot Analysis 8~10
2.5 Electrophysiology 10~14
2.6 Drug intervention 14~15
2.7 Statistical Analysis 15
3. Results
3.1 Study I
3.1.1 Expression of AT-1 R on HL-1 cardiomyocytes with or without collagen intervention 16
3.1.2 Effects of collagen on calcium homeostasis and regulatory proteins 16~17
3.1.3 Effects of collagen on the AP and associated membrane currents 17~18
3.2 Study II
3.2.1 Effects of collagen on the electrical activity of PV cardiomyocytes 18
3.2.2 Effects of collagen on membrane currents of PV cardiomyocytes 19
3.2.3 Roles of p38 MAPK in collagen-induced PV arrhythmogenesis 19~20
4. Discussion
4.1 Collagen can Modulate Calcium Homeostasis of Atrial Cardiomyocytes 21~22
4.2 Collagen can Modulate Electrophysiological Characteristics of Atrial and Pulmonary Cardiomyocytes 22~25
4.3 Collagen Modulates Electrophysiological Properties of Atrial Cardiomyocytes through RAS and MAPK Signaling 25~27
5. Summary and Conclusions 28
6. References 29~35
7. Figures 36~48
8. Oral presentation 49
1.Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI: Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circulation research 1988, 62(4):757-765.
2.Hobai IA, Hancox JC, Levi AJ: Inhibition by nickel of the L-type Ca channel in guinea pig ventricular myocytes and effect of internal cAMP. American journal of physiology Heart and circulatory physiology 2000, 279(2):H692-701.
3.van den Borne SW, Isobe S, Verjans JW, Petrov A, Lovhaug D, Li P, Zandbergen HR, Ni Y, Frederik P, Zhou J et al: Molecular imaging of interstitial alterations in remodeling myocardium after myocardial infarction. Journal of the American College of Cardiology 2008, 52(24):2017-2028.
4.Baudino TA, Carver W, Giles W, Borg TK: Cardiac fibroblasts: friend or foe? American journal of physiology Heart and circulatory physiology 2006, 291(3):H1015-1026.
5.Miner EC, Miller WL: A look between the cardiomyocytes: the extracellular matrix in heart failure. Mayo Clinic proceedings Mayo Clinic 2006, 81(1):71-76.
6.Boldt A, Wetzel U, Lauschke J, Weigl J, Gummert J, Hindricks G, Kottkamp H, Dhein S: Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart 2004, 90(4):400-405.
7.Skanes AC, Mandapati R, Berenfeld O, Davidenko JM, Jalife J: Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998, 98(12):1236-1248.
8.Crijns HJ, Tjeerdsma G, de Kam PJ, Boomsma F, van Gelder IC, van den Berg MP, van Veldhuisen DJ: Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. European heart journal 2000, 21(15):1238-1245.
9.Kucera JP, Rudy Y: Mechanistic insights into very slow conduction in branching cardiac tissue: a model study. Circulation research 2001, 89(9):799-806.
10.Janse MJ: Why does atrial fibrillation occur? European heart journal 1997, 18 Suppl C:C12-18.
11.Tanaka K, Zlochiver S, Vikstrom KL, Yamazaki M, Moreno J, Klos M, Zaitsev AV, Vaidyanathan R, Auerbach DS, Landas S et al: Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. Circulation research 2007, 101(8):839-847.
12.Steiner I, Hajkova P, Kvasnicka J, Kholova I: Myocardial sleeves of pulmonary veins and atrial fibrillation: a postmortem histopathological study of 100 subjects. Virchows Archiv : an international journal of pathology 2006, 449(1):88-95.
13.Everett THt, Olgin JE: Atrial fibrosis and the mechanisms of atrial fibrillation. Heart rhythm : the official journal of the Heart Rhythm Society 2007, 4(3 Suppl):S24-27.
14.Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR: Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 2005, 111(16):2025-2032.
15.Yeh YH, Wakili R, Qi XY, Chartier D, Boknik P, Kaab S, Ravens U, Coutu P, Dobrev D, Nattel S: Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circulation Arrhythmia and electrophysiology 2008, 1(2):93-102.
16.Schwartz MA: Spreading of human endothelial cells on fibronectin or vitronectin triggers elevation of intracellular free calcium. The Journal of cell biology 1993, 120(4):1003-1010.
17.Faury G, Usson Y, Robert-Nicoud M, Robert L, Verdetti J: Nuclear and cytoplasmic free calcium level changes induced by elastin peptides in human endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 1998, 95(6):2967-2972.
18.Chang SL, Chen YC, Yeh YH, Lin YK, Wu TJ, Lin CI, Chen SA, Chen YJ: Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks. Journal of cardiovascular electrophysiology 2011, 22(12):1378-1386.
19.Stambler BS, Fenelon G, Shepard RK, Clemo HF, Guiraudon CM: Characterization of sustained atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. Journal of cardiovascular electrophysiology 2003, 14(5):499-507.
20.Davis MJ, Wu X, Nurkiewicz TR, Kawasaki J, Gui P, Hill MA, Wilson E: Regulation of ion channels by integrins. Cell biochemistry and biophysics 2002, 36(1):41-66.
21.Yin L, Bien H, Entcheva E: Scaffold topography alters intracellular calcium dynamics in cultured cardiomyocyte networks. American journal of physiology Heart and circulatory physiology 2004, 287(3):H1276-1285.
22.Krishnamurthy P, Subramanian V, Singh M, Singh K: Beta1 integrins modulate beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling. Hypertension 2007, 49(4):865-872.
23.Meredith JE, Jr., Winitz S, Lewis JM, Hess S, Ren XD, Renshaw MW, Schwartz MA: The regulation of growth and intracellular signaling by integrins. Endocrine reviews 1996, 17(3):207-220.
24.Hsueh WA, Law RE, Do YS: Integrins, adhesion, and cardiac remodeling. Hypertension 1998, 31(1 Pt 2):176-180.
25.Aikawa R, Nagai T, Kudoh S, Zou Y, Tanaka M, Tamura M, Akazawa H, Takano H, Nagai R, Komuro I: Integrins play a critical role in mechanical stress-induced p38 MAPK activation. Hypertension 2002, 39(2):233-238.
26.Zhao A, Alvin Z, Laurence G, Li C, Haddad GE: Cross-talk between MAPKs and PI-3K pathways alters the functional density of I(K) channels in hypertrophied hearts. Ethnicity & disease 2010, 20(1 Suppl 1):S1-219-224.
27.Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, Saffitz J, Chien K, Xiao RP, Kass DA et al: The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America 2001, 98(21):12283-12288.
28.Claycomb WC, Lanson NA, Jr., Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ, Jr.: HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proceedings of the National Academy of Sciences of the United States of America 1998, 95(6):2979-2984.
29.Gramley F, Lorenzen J, Knackstedt C, Rana OR, Saygili E, Frechen D, Stanzel S, Pezzella F, Koellensperger E, Weiss C et al: Age-related atrial fibrosis. Age 2009, 31(1):27-38.
30.Bouillier H, Samain E, Rucker-Martin C, Renaud JF, Safar M, Dagher G: Effect of extracellular matrix elements on angiotensin II-induced calcium release in vascular smooth muscle cells from normotensive and hypertensive rats. Hypertension 2001, 37(6):1465-1472.
31.Chen YC, Pan NH, Cheng CC, Higa S, Chen YJ, Chen SA: Heterogeneous expression of potassium currents and pacemaker currents potentially regulates arrhythmogenesis of pulmonary vein cardiomyocytes. Journal of cardiovascular electrophysiology 2009, 20(9):1039-1045.
32.Chen YJ, Chen YC, Tai CT, Yeh HI, Lin CI, Chen SA: Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins. British journal of pharmacology 2006, 147(1):12-22.
33.Wongcharoen W, Chen YC, Chen YJ, Lin CI, Chen SA: Effects of aging and ouabain on left atrial arrhythmogenicity. Journal of cardiovascular electrophysiology 2007, 18(5):526-531.
34.Weinbrenner C, Liu GS, Cohen MV, Downey JM: Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. Journal of molecular and cellular cardiology 1997, 29(9):2383-2391.
35.Clerk A, Sugden PH: The p38-MAPK inhibitor, SB203580, inhibits cardiac stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs). FEBS letters 1998, 426(1):93-96.
36.Chang SH, Chen YC, Chiang SJ, Higa S, Cheng CC, Chen YJ, Chen SA: Increased Ca(2+) sparks and sarcoplasmic reticulum Ca(2+) stores potentially determine the spontaneous activity of pulmonary vein cardiomyocytes. Life sciences 2008, 83(7-8):284-292.
37.Bassani JW, Bassani RA, Bers DM: Calibration of indo-1 and resting intracellular [Ca]i in intact rabbit cardiac myocytes. Biophysical journal 1995, 68(4):1453-1460.
38.Chen YJ, Chen YC, Wongcharoen W, Lin CI, Chen SA: Effect of K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes. British journal of pharmacology 2008, 153(5):915-925.
39.Wongcharoen W, Chen YC, Chen YJ, Chang CM, Yeh HI, Lin CI, Chen SA: Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity. Cardiovascular research 2006, 70(3):497-508.
40.Lin YK, Chen YC, Chen JH, Chen SA, Chen YJ: Adipocytes modulate the electrophysiology of atrial myocytes: implications in obesity-induced atrial fibrillation. Basic research in cardiology 2012, 107(5):293.
41.Chua SK, Chang PC, Maruyama M, Turker I, Shinohara T, Shen MJ, Chen Z, Shen C, Rubart-von der Lohe M, Lopshire JC et al: Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. Circulation research 2011, 108(8):971-979.
42.Suenari K, Cheng CC, Chen YC, Lin YK, Nakano Y, Kihara Y, Chen SA, Chen YJ: Effects of ivabradine on the pulmonary vein electrical activity and modulation of pacemaker currents and calcium homeostasis. Journal of cardiovascular electrophysiology 2012, 23(2):200-206.
43.Nattel S, Maguy A, Le Bouter S, Yeh YH: Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiological reviews 2007, 87(2):425-456.
44.Sridhar A, Nishijima Y, Terentyev D, Khan M, Terentyeva R, Hamlin RL, Nakayama T, Gyorke S, Cardounel AJ, Carnes CA: Chronic heart failure and the substrate for atrial fibrillation. Cardiovascular research 2009, 84(2):227-236.
45.Franz MR, Karasik PL, Li C, Moubarak J, Chavez M: Electrical remodeling of the human atrium: similar effects in patients with chronic atrial fibrillation and atrial flutter. Journal of the American College of Cardiology 1997, 30(7):1785-1792.
46.Yang Z, Shen W, Rottman JN, Wikswo JP, Murray KT: Rapid stimulation causes electrical remodeling in cultured atrial myocytes. Journal of molecular and cellular cardiology 2005, 38(2):299-308.
47.Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A: Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997, 96(4):1180-1184.
48.Suenari K, Chen YC, Kao YH, Cheng CC, Lin YK, Chen YJ, Chen SA: Discrepant electrophysiological characteristics and calcium homeostasis of left atrial anterior and posterior myocytes. Basic research in cardiology 2011, 106(1):65-74.
49.Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C: Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 2007, 116(13):1449-1457.
50.Song Y, Shryock JC, Belardinelli L: A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes. American journal of physiology Heart and circulatory physiology 2009, 297(4):H1254-1262.
51.Kiyosue T, Arita M: Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circulation research 1989, 64(2):389-397.
52.Wongcharoen W, Chen YC, Chen YJ, Chen SY, Yeh HI, Lin CI, Chen SA: Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents. Heart rhythm : the official journal of the Heart Rhythm Society 2007, 4(10):1338-1349.
53.Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, Zhang Z, Singapuri A, Albert TR, Rajagopal AV et al: Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. The Journal of physiology 2009, 587(Pt 5):1087-1100.
54.Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S: Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circulation research 1997, 81(4):512-525.
55.Ozgen N, Dun W, Sosunov EA, Anyukhovsky EP, Hirose M, Duffy HS, Boyden PA, Rosen MR: Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovascular research 2007, 75(4):758-769.
56.Christ T, Boknik P, Wohrl S, Wettwer E, Graf EM, Bosch RF, Knaut M, Schmitz W, Ravens U, Dobrev D: L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation 2004, 110(17):2651-2657.
57.Litovsky SH, Antzelevitch C: Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium. Circulation research 1990, 67(3):615-627.
58.Chen YJ, Chen SA, Chen YC, Yeh HI, Chan P, Chang MS, Lin CI: Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation 2001, 104(23):2849-2854.
59.Lai LP, Su MJ, Lin JL, Tsai CH, Lin FY, Chen YS, Hwang JJ, Huang SK, Tseng YZ, Lien WP: Measurement of funny current (I(f)) channel mRNA in human atrial tissue: correlation with left atrial filling pressure and atrial fibrillation. Journal of cardiovascular electrophysiology 1999, 10(7):947-953.
60.Zicha S, Fernandez-Velasco M, Lonardo G, L''Heureux N, Nattel S: Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovascular research 2005, 66(3):472-481.
61.Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ: Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 2001, 103(6):789-791.
62.Sadoshima J, Xu Y, Slayter HS, Izumo S: Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993, 75(5):977-984.
63.Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, Anversa P: Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. The Journal of clinical investigation 1998, 101(7):1326-1342.
64.Kojima M, Shiojima I, Yamazaki T, Komuro I, Zou Z, Wang Y, Mizuno T, Ueki K, Tobe K, Kadowaki T et al: Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro. Circulation 1994, 89(5):2204-2211.
65.Tsuneyoshi H, Oriyanhan W, Kanemitsu H, Shiina R, Nishina T, Matsuoka S, Ikeda T, Komeda M: Does the beta2-agonist clenbuterol help to maintain myocardial potential to recover during mechanical unloading? Circulation 2005, 112(9 Suppl):I51-56.
66.Lerman BB, Engelstein ED, Burkhoff D: Mechanoelectrical feedback: role of beta-adrenergic receptor activation in mediating load-dependent shortening of ventricular action potential and refractoriness. Circulation 2001, 104(4):486-490.
67.Brancaccio M, Hirsch E, Notte A, Selvetella G, Lembo G, Tarone G: Integrin signalling: the tug-of-war in heart hypertrophy. Cardiovascular research 2006, 70(3):422-433.
68.Haq S, Choukroun G, Lim H, Tymitz KM, del Monte F, Gwathmey J, Grazette L, Michael A, Hajjar R, Force T et al: Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 2001, 103(5):670-677.
69.Hannigan GE, Coles JG, Dedhar S: Integrin-linked kinase at the heart of cardiac contractility, repair, and disease. Circulation research 2007, 100(10):1408-1414.
70.Cheng Q, Ross RS, Walsh KB: Overexpression of the integrin beta(1A) subunit and the beta(1A) cytoplasmic domain modifies the beta-adrenergic regulation of the cardiac L-type Ca(2+)current. Journal of molecular and cellular cardiology 2004, 36(6):809-819.
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