Defective Ca2+ Handling Proteins Regulation During Heart Failure

Physiological Research - Trang 27-37 - 2011
S.-T. HU1,2, Gang Liu1, Y.-F. SHEN1, Yongliang Wang1, Yansong Tang1, Y.-J. YANG1
1Department of Biophysics, Second Military Medical University, Shanghai, People’s Republic of China
2Department of Physiology, Basic Medical Science College, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China

Tóm tắt

Abnormal release of Ca2+ from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction in heart failure (HF). We previously demonstrated that RyR2 macromolecular complexes from HF rat were significantly more depleted of FK506 binding protein (FKBP12.6). Here we assessed expression of key Ca2+ handling proteins and measured SR Ca2+ content in control and HF rat myocytes. Direct measurements of SR Ca2+ content in permeabilized cardiac myocytes demonstrated that SR luminal [Ca2+] is markedly lowered in HF (HF: ΔF/F0 = 26.4±1.8, n=12; control: ΔF/F0 = 49.2±2.9, n=10; P<0.01). Furthermore, we demonstrated that the expression of RyR2 associated proteins (including calmodulin, sorcin, calsequestrin, protein phosphatase 1, protein phosphatase 2A), Ca2+ATPase (SERCA2a), PLB phosphorylation at Ser16 (PLB-S16), PLB phosphorylation at Thr17 (PLB-T17), L-type Ca2+ channel (Cav1.2) and Na+-Ca2+ exchanger (NCX) were significantly reduced in rat HF. Our results suggest that systolic SR reduced Ca2+ release and diastolic SR Ca2+ leak (due to defective protein-protein interaction between RyR2 and its associated proteins) along with reduced SR Ca2+ uptake (due to down-regulation of SERCA2a, PLB-S16 and PLB-T17), abnormal Ca2+ extrusion (due to down-regulation of NCX) and defective Ca2+-induced Ca2+ release (due to down-regulation of Cav1.2) could contribute to HF.

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Tài liệu tham khảo

BASSANI JW, BASSANI RA, BERS DM: Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms. J Physiol (Lond) 476: 279-293, 1994.

BERS DM: Macromolecular complexes regulating cardiac ryanodine receptor function. J Mol Cell Cardiol 37: 417429, 2004.

DESANTIAGO J, MAIER LS, BERS DM: Frequency-dependent acceleration of relaxation in the heart depends on CaMKII, but not phospholamban. J Mol Cell Cardiol 34: 975-984, 2002.

GUO T, ZHANG T, MESTRIL R, BERS DM: Ca2+/calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. Circ Res 99: 398-406, 2006.

GYÖRKE I, HESTER N, JONES LR, GYÖRKE S: The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys J 86: 2121-2128, 2004.

HASENFUSS G: Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37: 279-289, 1998.

HOBAI IA, O’ROURKE B: Decreased sarcoplasmic reticulum calcium content is responsible for defective excitationcontraction coupling in canine heart failure. Circulation 103: 1577-1584, 2001.

HOUSER SR, MARGULIES KB: Is depressed myocyte contractility centrally involved in heart failure? Circ Res 92: 350-358, 2003.

JAYARAMAN T, BRILLANTES AM., TIMERMAN AP, FLEISCHER S, ERDJUMENT-BROMAGE H, EMPST P., MARKS AR: FK506 binding protein associated with the calcium release channel (ryanodine receptor). J Biol Chem 267: 9474-9477, 1992.

LI L, DESANTIAGO J, CHU G, KRANIAS EG, BERS DM: Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol 278: H769-H779, 2000.

LINDNER M, ERDMANN E, BEUCKELMAN DJ: Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol 30: 743-749, 1998.

LITWIN SE, BRIDGE JH: Enhanced Na+-Ca2+ exchange in the infarcted heart. Implications for excitation-contraction coupling. Circ Res 81: 1083-1093, 1997.

MARX SO, REIKEN S, HISAMATSU Y, JAYARAMAN T, BURKHOFF D, ROSEMBLIT N, MARKS AR: PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor) defective regulation in failing hearts. Cell 101: 365-376, 2000.

MEYER M., SCHILLINGER W, PIESKE B, HOLUBARSCH C, HEILMANN C, POSIVAL H, KUWAJIMA G, MIKOSHIBA K, JUST H, HASENFUSS G: Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92: 778-784, 1995.

NAKAYA H, TOHSE N, TAKEDA Y, KANNO M: Effects of MS-551, a new class antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes. Br J Pharmacol 109: 157-163, 1993.

OHMOTO-SEKINE Y, UEMURA H, TAMAGAWA M, NAKAYA H: Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells. Br J Pharmacol 126: 751-761, 1999.

PIACENTINO V III, WEBER CR, CHEN X, WEISSER-THOMAS J, MARGULIES KB, BERS DM, HOUSER SR: Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res 92: 651-658, 2003.

PIESKE B, HOUSER SR: [Na+]i handling in the failing human heart. Cardiovasc Res 57: 874-886, 2003.

POGWIZD SM, SCHLOTTHAUER K, LI L, YUAN W, BERS DM: Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual betaadrenergic responsiveness. Circ Res 88: 1159-1167, 2001.

SHANNON TR, POGWIZD SM, BERS DM: Elevated sarcoplasmic reticulum Ca2+ leak in intact ventricular myocytes from rabbits in heart failure. Circ Res 93: 592-594, 2003.

SIPIDO KR, MAES M, VAN DE WERF F: Low efficiency of Ca2+ entry through the Na+-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na+-Ca2+ exchange. Circ Res 81: 1034-1044, 1997.

SIPIDO KR, VOLDERS PG, DE GROOT SH, VERDONCK F, VAN DE WERF F, WELLENS HJ, VOS MA: Enhanced Ca2+ release and Na+-Ca2+ exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis. Circulation 102: 2137-2144, 2000.

TANONAKA K, FURUHAMA KI, YOSHIDA H, KAKUTA K, MIYAMOTO Y, TAKEO S, TOGA W: Protective effect of heat shock protein 72 on contractile function in the perfused failing heart. Am J Physiol 281: H215H222, 2001.

TERENTYEV D, VIATCHENKO-KARPINSKI S, VEDAMOORTHYRAO S, ODURU S, GYÖRKE I, WILLIAMS SC, GYÖRKE S: Protein-protein interactions between triadin and calsequestrin are involved in modulation of sarcoplasmic reticulum calcium release in cardiac myocytes. J Physiol (Lond) 583: 71-80, 2007.

VAN ROOIJ E, DOEVENDANS PA, CRIJNS HJ, HEENEMAN S, LIPS DJ, VAN BILSEN M, WILLIAMS RS, OLSON EN, BASSEL-DUBY R, ROTHERMEL BA, DE WINDT LJ: MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction. Circ Res 94: e18-e26, 2004.

WEHRENS XH, LEHNART SE, HUANG F, VEST JA, REIKEN SR, MOHLER PJ, SUN J, GUATIMOSIM S, SONG LS, ROSEMBLIT N, D'ARMIENTO JM, NAPOLITANO C, MEMMI M, PRIORI SG, LEDERER WJ, MARKS AR: FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 113: 829-840, 2003.

XIAO B, JIANG MT, ZHAO M, YANG D, SUYHERLAND C, LAI FA, WALSH MP, WARLTIER DC, CHENG H, CHEN SR: Characterization of a novel PKA phosphorylation site, serine-2030, reveals no PKA hyperphosphorylation of the cardiac ryanodine receptor in canine heart failure. Circ Res 96: 847-855, 2005.

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Physiological Research

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