Published online before print January 2, 2003, doi: 10.1161/01.RES.0000054624.03539.B4
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Reports |
ß-Adrenergic Receptor–Stimulated Apoptosis in Cardiac Myocytes Is Mediated by Reactive Oxygen Species/c-Jun NH2-Terminal Kinase–Dependent Activation of the Mitochondrial Pathway
From the Myocardial Biology Unit and Cardiovascular Medicine Section, Boston University Medical Center, Boston, Mass. Present address for K.S. is the Department of Physiology, East Tennessee State University, Johnson City, Tenn.
Correspondence to Wilson S. Colucci, MD, Boston University Medical Center, 88 East Newton St, Boston, MA 02118. E-mail wilson.colucci{at}bmc.org
Abstract
Stimulation of ß-adrenergic receptors (ßARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating ßAR-stimulated apoptosis is not known. Stimulation of ßARs with norepinephrine (10 µmol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 µmol/L) and Euk-134 decreased ßAR-stimulated apoptosis by 89±6% and 76±10%, respectively. Infection with an adenovirus expressing catalase decreased ßAR-stimulated apoptosis by 82±15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 µmol/L) decreased ßAR-stimulated apoptosis by 76±8%, and the caspase inhibitor zVAD-fmk (25 µmol/L) decreased ßAR-stimulated apoptosis by 62±11%. ßAR-stimulated cytochrome c release was inhibited by MnTMPyP. ßAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited ßAR-stimulated apoptosis by 81±12%, and the JNK inhibitor SP600125 inhibited both ßAR-stimulated apoptosis and cytochrome c release. Thus, ßAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.
Key Words: apoptosis • ß-adrenergic receptors • c-Jun NH2-terminal kinase • mitochondria • reactive oxygen species
Beta-adrenergic receptor (ßAR) stimulation in adult rat ventricular myocytes (ARVMs) causes apoptosis,1–5 which involves caspase activation.4 However, little is known about the signals proximal to caspase. Reactive oxygen species (ROS) can cause myocyte apoptosis,6–8 and ROS may mediate myocyte apoptosis in response to remodeling stimuli.9,10 ROS can induce myocyte apoptosis through c-Jun NH2-terminal kinase (JNK)-dependent activation of a mitochondrial pathway.11 We therefore tested the roles of ROS, JNK, and mitochondria in mediating ßAR-stimulated cardiac myocyte apoptosis.
Materials and Methods
Isolation of ARVMs
ARVMs prepared as previously described1 were plated 30 to 50 cells/mm2 on 100-mm plastic culture dishes for Western blotting or 40x22 mm2 glass coverslips precoated with laminin (1 µg/cm2, Becton-Dickinson) for TUNEL staining.
Cell Treatments
L-Norepinephrine (NE; 10 µmol/L; Sigma) was added for 24 hours (TUNEL), 6 hours (cytochrome c), or 15 minutes (JNK). Prazosin (PZ; 0.1 µmol/L; Sigma) was added 30 minutes before NE. All plates were supplemented with ascorbic acid (100 µmol/L). Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 µmol/L; Calbiochem), Euk-13412 (Euk; 50 µmol/L; Eukarion), bongkrekic acid (BA; 50 µmol/L; Calbiochem), zVAD-fmk (zVAD; 25 µmol/L, Calbiochem), and SP600125 (SP; 2 µmol/L; Calbiochem) were added 30 minutes before NE.
Western Blotting for Cytochrome c and Phospho-JNK
Mitochondrial cytochrome c release was determined according to Aoki et al.11 Phospho-JNK and TUNEL staining were determined as previously described.13
Adenoviral Infection
ARVMs were infected with adenovirus expressing ß-galactosidase (10 multiplicity of infection [MOI]), catalase (50 MOI; ATCC), or dominant-negative JNK (10 MOI; the T183A, Y185F JNK1 mutant,14 courtesy of R. Davis, University of Massachusetts, Worcester, Mass) 48 hours before addition of NE.
Statistical Analysis
All data are mean±SEM. Differences across multiple conditions were tested by one-way ANOVA for repeated measures. Comparisons between conditions were tested by Student’s unpaired t test using the Bonferroni correction for multiple comparisons.
Results
ßAR-Stimulated Apoptosis Is ROS-Dependent and Involves the Mitochondrial Permeability Transition Pore and Caspase Activation
Under control conditions, 4% to 7% of cells were apoptotic as assessed by TUNEL staining. ßAR stimulation with NE in the presence of PZ (NE/PZ) for 24 hours increased the number of apoptotic myocytes by 3.6±0.2-fold (Figure 1A). The superoxide dismutase (SOD)/catalase mimetics MnTMPyP and Euk decreased the magnitude of ßAR-stimulated apoptosis by 89±6% and 76±10%, respectively (Figure 1A). Likewise, infection with an adenovirus expressing catalase decreased ßAR-stimulated apoptosis by 82±15% (Figure 1B). Bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore,15 decreased ßAR-stimulated apoptosis by 76±8% (Figure 1A). The caspase inhibitor zVAD-fmk decreased ßAR-stimulated apoptosis by 62±11% (Figure 1A).
|
P<0.001 vs NE/PZ+Lac-Z. C, ROS dependence of ßAR-stimulated cytochrome c mobilization. Cytochrome c was measured by Western blotting in the cytosolic fraction. NE/PZ caused a 2.1±0.2-fold increase in cytosolic cytochrome c, which was inhibited by MnTMPyP (10 µmol/L). Data are from 8 experiments. *P<0.001 vs Control;
ßAR Stimulation Causes ROS-Dependent Mitochondrial Cytochrome c Release
ßAR stimulation (6 hours) increased cytosolic cytochrome c by 2.1±0.2-fold (Figure 1C). MnTMPyP decreased ßAR-stimulated cytochrome c release to 1.4±0.3-fold (Figure 1C).
ßAR-Stimulated Apoptosis and Cytochrome c Release Are JNK-Dependent
ßAR stimulation (15 minutes) caused a 2.3±0.4-fold increase in JNK activity. MnTMPyP decreased ßAR-stimulated JNK activation to 1.0±0.3-fold (Figure 2A). The JNK inhibitor SP60012516 decreased ßAR-stimulated apoptosis to 1.3±0.1-fold (Figure 2B) and decreased ßAR-stimulated cytochrome c release to 1.6±0.4-fold (P<0.05; n=6). Likewise, infection with an adenovirus expressing dominant-negative JNK, which inhibited JNK activation by 
70% (data not shown), decreased ßAR-stimulated apoptosis by 81±12% (Figure 2C).
|
Discussion
We1,2 and others3–5 have shown that ßAR stimulation causes apoptosis in ARVMs. In the present study, ßAR-stimulated apoptosis was inhibited by SOD/catalase mimetics or overexpression of catalase, thereby demonstrating that ROS play a necessary role in ßAR-stimulated apoptosis and suggesting that the responsible ROS is H2O2 or a derivative.
We found that ßAR stimulation caused mitochondrial cytochrome c release, which was ROS-dependent, and that the mitochondrial permeability transition pore inhibitor bongkrekic acid15 decreased ßAR-stimulated apoptosis, thus implicating the mitochondrial pathway. ROS are known to cause mitochondrial cytochrome c release in cardiac myocytes.8,11
ßAR stimulation in ARVMs causes activation of JNK, p38, and to a lesser extent, extracellular signal-regulated kinase (ERK).13 In the present study, ßAR-stimulated JNK activation was inhibited by MnTMPyP, thus indicating that it is ROS-dependent. Further, infection with an adenovirus expressing dominant-negative JNK14 inhibited ßAR-stimulated apoptosis, and the JNK inhibitor SP6001216 prevented both ßAR-stimulated apoptosis and cytochrome c release. Thus, ßAR activation of the mitochondrial death pathway requires the ROS-dependent activation of JNK. JNK can associate with mitochondria and mediate activation of the mitochondrial death pathway in cardiac myocytes in response to H2O2.11 In contrast, JNK may exert antiapoptotic effects in neonatal rat cardiac myocytes exposed to nitric oxide,17 suggesting that the role of JNK is cell-type and/or context-dependent. We previously found that ßAR-stimulated apoptosis was increased by inhibition of p38 and not affected by inhibition of ERK.13
It is now recognized that ROS play an important role in signal transduction.18 We previously found that 
-adrenergic receptor (AR) stimulation causes ROS-dependent activation of the ras-raf-MEK-ERK1/2 cascade leading to hypertrophy.19,20 In contrast to ßAR stimulation, AR stimulation does not cause myocyte apoptosis.19 We have also found that ROS can mediate either hypertrophy or apoptosis in cardiac myocytes in response to mechanical strain, depending on the magnitude of strain.10 That AR versus ßAR and different amplitudes of mechanical strain link via ROS to distinct myocyte phenotypes suggests that qualitative and/or quantitative differences in ROS are critical determinants of ROS signaling in cardiac myocytes. The source of ROS that links ßAR stimulation to apoptosis remains to be determined but may involve mitochondria, xanthine oxidase, NADPH oxidase, nitric oxide synthase, and/or cyclooxygenase.
These findings indicate that ROS play a central role in the regulation of myocyte apoptosis via JNK-dependent activation of the mitochondrial death pathway. ROS are thus a potential new target for the prevention of myocardial failure.
Acknowledgments
This work was supported by NIH grants HL61639 and HL20612 (to W.S.C.), HL057947 (to K.S.), HL03878 (to D.B.S.), and HL07224 (to S.K.); a grant from the Swiss National Science Foundation (to A.R.); and a Merit grant from the Department of Veterans Affairs (to K.S.).
Received October 29, 2002; revision received December 17, 2002; accepted December 17, 2002.
References
1. Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the ß-adrenergic pathway. Circulation. 1998; 98: 1329–1334.
2. Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of ß1- and ß2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation. 1999; 100: 2210–2212.
3. Iwai-Kanai E, Hasegawa K, Araki M, Kakita T, Morimoto T, Sasayama S. - and ß-Adrenergic pathways differentially regulate cell type–specific apoptosis in rat cardiac myocytes. Circulation. 1999; 100: 305–311.
4. Zaugg M, Xu W, Lucchinetti E, Shafiq SA, Jamali NZ, Siddiqui MA. ß-Adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation. 2000; 102: 344–350.
5. Shizukuda Y, Buttrick PM, Geenen DL, Borczuk AC, Kitsis RN, Sonnenblick EH. ß-Adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol. 1998; 275: H961–H968.[Medline] [Order article via Infotrieve]
6. Turner NA, Xia F, Azhar G, Zhang X, Liu L, Wei JY. Oxidative stress induces DNA fragmentation and caspase activation via the c-Jun NH2-terminal kinase pathway in H9c2 cardiac muscle cells. J Mol Cell Cardiol. 1998; 30: 1789–1801.[CrossRef][Medline] [Order article via Infotrieve]
7. Siwik DA, Tzortzis JD, Pimental DR, Chang DL, Pagano PJ, Singh K, Sawyer DB, Colucci WS. Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circ Res. 1999; 85: 147–153.
8. von Harsdorf R, Li PF, Dietz R. Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation. 1999; 99: 2934–2941.
9. Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 2002; 34: 379–388.[CrossRef][Medline] [Order article via Infotrieve]
10. Pimentel DR, Amin JK, Xiao L, Miller T, Viereck J, Oliver-Krasinski J, Baliga R, Wang J, Siwik DA, Singh K, Pagano P, Colucci WS, Sawyer DB. Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circ Res. 2001; 89: 453–460.
11. Aoki H, Kang PM, Hampe J, Yoshimura K, Noma T, Matsuzaki M, Izumo S. Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes. J Biol Chem. 2002; 277: 10244–10250.
12. Rong Y, Doctrow SR, Tocco G, Baudry M. EUK-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proc Natl Acad Sci U S A. 1999; 96: 9897–9902.
13. Communal C, Colucci WS, Singh K. p38 Mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against ß-adrenergic receptor-stimulated apoptosis. J Biol Chem. 2000; 275: 19395–19400.
14. Xia Z, Dickens M, Raingeard J, Davis RJ, Greengerg ME. Opposing effects of ERKs and JNK-38 MAP kinase on apoptosis. Science. 1995; 270: 1326–1331.
15. Zamzami N, Marchetti P, Castedo M, Hirsch T, Susin SA, Masse B, Kroemer G. Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett. 1996; 384: 53–57.[CrossRef][Medline] [Order article via Infotrieve]
16. Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A. 2001; 98: 13681–13686.
17. Dougherty CJ, Kubasiak LA, Prentice H, Andreka P, Bishopric NH, Webster KA. Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress. Biochem J. 2002; 362: 561–571.[CrossRef][Medline] [Order article via Infotrieve]
18. Finkel T. Redox-dependent signal transduction. FEBS Lett. 2000; 476: 52–54.[CrossRef][Medline] [Order article via Infotrieve]
19. Amin JK, Xiao L, Pimental DR, Pagano PJ, Singh K, Sawyer DB, Colucci WS. Reactive oxygen species mediate -adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol. 2001; 33: 131–139.[CrossRef][Medline]
[Order article via Infotrieve]
20. Xiao L, Pimentel DR, Wang J, Singh K, Colucci WS, Sawyer DB. Role of reactive oxygen species and NAD(P)H oxidase in 1-adrenoceptor signaling in adult rat cardiac myocytes. Am J Physiol Cell Physiol. 2002; 282: C926–C934.
This article has been cited by other articles:
 |
|
 |
|
  O. M. Hess, W. McKenna, and H.-P. Schultheiss CHAPTER 18 Myocardial Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Yano, D. Suzuki, M. Endoh, A. Tseng, J. P. Stabila, B. G. McGonnigal, T. C. Zhao, J. F. Padbury, and Y.-T. Tseng {beta}-Adrenergic Receptor Mediated Protection against Doxorubicin-Induced Apoptosis in Cardiomyocytes: The Impact of High Ambient Glucose Endocrinology, December 1, 2008; 149(12): 6449 - 6461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yu, S.-S. Sheu, J. L. Robotham, and Y. Yoon Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species Cardiovasc Res, July 15, 2008; 79(2): 341 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sabri, K. Rafiq, R. Seqqat, M. A. Kolpakov, R. Dillon, and L. J. Dell'italia Sympathetic Activation Causes Focal Adhesion Signaling Alteration in Early Compensated Volume Overload Attributable to Isolated Mitral Regurgitation in the Dog Circ. Res., May 9, 2008; 102(9): 1127 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Tran, P. Andreka, C. O. Rodrigues, K. A. Webster, and N. H. Bishopric Jun Kinase Delays Caspase-9 Activation by Interaction with the Apoptosome J. Biol. Chem., July 13, 2007; 282(28): 20340 - 20350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, B. Chandrasekar, Y. Gu, J. Luo, T. Hamid, B. G. Hill, and S. D. Prabhu Downregulation of CuZn-superoxide dismutase contributes to {beta}-adrenergic receptor-mediated oxidative stress in the heart Cardiovasc Res, June 1, 2007; 74(3): 445 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. E. Osadchii, G. R. Norton, R. McKechnie, D. Deftereos, and A. J. Woodiwiss Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic beta-adrenoreceptor activation Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1898 - H1905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Milano, S. Morel, C. Bonny, M. Samaja, L. K. von Segesser, P. Nicod, and G. Vassalli A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1828 - H1835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Krishnamurthy, V. Subramanian, M. Singh, and K. Singh {beta}1 Integrins Modulate {beta}-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling Hypertension, April 1, 2007; 49(4): 865 - 872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J T Parissis, S Adamopoulos, D Farmakis, G Filippatos, I Paraskevaidis, F Panou, E Iliodromitis, and D Th Kremastinos Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure Heart, December 1, 2006; 92(12): 1768 - 1772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-C. Fan, Q. Yuan, G. Song, Y. Wang, G. Chen, J. Qian, X. Zhou, Y. J. Lee, M. Ashraf, and E. G. Kranias Small Heat-Shock Protein Hsp20 Attenuates {beta}-Agonist-Mediated Cardiac Remodeling Through Apoptosis Signal-Regulating Kinase 1 Circ. Res., November 24, 2006; 99(11): 1233 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Voisin, A. E. Firar, V. Avondo, and M. Laburthe Orexin-Induced Apoptosis: The Key Role of the Seven-Transmembrane Domain Orexin Type 2 Receptor Endocrinology, October 1, 2006; 147(10): 4977 - 4984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hu, X. Jiao, E. Gao, W. J. Koch, S. Sharifi-Azad, Z. Grunwald, X. L. Ma, and J.-Z. Sun Chronic beta-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 469 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Arora, F. Alfayoumi, and V. Srinivasan Transient Left Ventricular Apical Ballooning After Cocaine Use: Is Catecholamine Cardiotoxicity the Pathologic Link? Mayo Clin. Proc., June 1, 2006; 81(6): 829 - 832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Menon, M. Singh, R. S. Ross, J. N. Johnson, and K. Singh {beta}-Adrenergic receptor-stimulated apoptosis in adult cardiac myocytes involves MMP-2-mediated disruption of {beta}1 integrin signaling and mitochondrial pathway Am J Physiol Cell Physiol, January 1, 2006; 290(1): C254 - C261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-T. Tseng, N. Yano, A. Rojan, J. P. Stabila, B. G. McGonnigal, V. Ianus, R. Wadhawan, and J. F. Padbury Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute {beta}-adrenergic stimulation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1834 - H1842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kaiser, Q. Liang, O. Bueno, Y. Huang, T. Lackey, R. Klevitsky, T. E. Hewett, and J. D. Molkentin Genetic Inhibition or Activation of JNK1/2 Protects the Myocardium from Ischemia-Reperfusion-induced Cell Death in Vivo J. Biol. Chem., September 23, 2005; 280(38): 32602 - 32608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Isabelle, C. Monteil, F. Moritz, B. Dautreaux, J.-P. Henry, V. Richard, P. Mulder, and C. Thuillez Role of {alpha}1-adrenoreceptors in cocaine-induced NADPH oxidase expression and cardiac dysfunction Cardiovasc Res, September 1, 2005; 67(4): 699 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Menon, M. Singh, and K. Singh Matrix metalloproteinases mediate {beta}-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes Am J Physiol Cell Physiol, July 1, 2005; 289(1): C168 - C176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. J. Buermans, E. M. Redout, A. E. Schiel, R. J. P. Musters, M. Zuidwijk, P. P. Eijk, C. van Hardeveld, S. Kasanmoentalib, F. C. Visser, B. Ylstra, et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure Physiol Genomics, May 11, 2005; 21(3): 314 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Brown, P. A. Goldberg, J. G. Selter, H. S. Cabin, N. J. Marieb, R. Udelsman, and J. F. Setaro Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 563 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Zhang, S. Kimura, A. Nishiyama, T. Shokoji, M. Rahman, L. Yao, Y. Nagai, Y. Fujisawa, A. Miyatake, and Y. Abe Cardiac oxidative stress in acute and chronic isoproterenol-infused rats Cardiovasc Res, January 1, 2005; 65(1): 230 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kuramochi, G. M. Cote, X. Guo, N. K. Lebrasseur, L. Cui, R. Liao, and D. B. Sawyer Cardiac Endothelial Cells Regulate Reactive Oxygen Species-induced Cardiomyocyte Apoptosis through Neuregulin-1{beta}/erbB4 Signaling J. Biol. Chem., December 3, 2004; 279(49): 51141 - 51147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rouet-Benzineb, C. Rouyer-Fessard, A. Jarry, V. Avondo, C. Pouzet, M. Yanagisawa, C. Laboisse, M. Laburthe, and T. Voisin Orexins Acting at Native OX1 Receptor in Colon Cancer and Neuroblastoma Cells or at Recombinant OX1 Receptor Suppress Cell Growth by Inducing Apoptosis J. Biol. Chem., October 29, 2004; 279(44): 45875 - 45886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ito, T. Adachi, D. R. Pimentel, Y. Ido, and W. S. Colucci Statins Inhibit {beta}-Adrenergic Receptor-Stimulated Apoptosis in Adult Rat Ventricular Myocytes via a Rac1-Dependent Mechanism Circulation, July 27, 2004; 110(4): 412 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Mao, F. Qin, C. Iwai, R. Vulapalli, P. C. Keng, and C.-s. Liang Extracellular norepinephrine reduces neuronal uptake of norepinephrine by oxidative stress in PC12 cells Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H29 - H39. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-C. Fan, G. Chu, B. Mitton, Q. Song, Q. Yuan, and E. G. Kranias Small Heat-Shock Protein Hsp20 Phosphorylation Inhibits {beta}-Agonist-Induced Cardiac Apoptosis Circ. Res., June 11, 2004; 94(11): 1474 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Fu, C.-S. Chi, S.-C. Yin, B. Hwang, Y.-T. Chiu, and S.-L. Hsu Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF{alpha}-caspase signaling pathway Cardiovasc Res, June 1, 2004; 62(3): 558 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mukherjee, W. M. Yarbrough, E. S. Reese, J. S. Leiser, J. A. Sample, J. T. Mingoia, A. E. Hardin, R. E. Stroud, J. E. McLean, J. W. Hendrick, et al. Myocyte contractility with caspase inhibition and simulated hyperkalemic cardioplegic arrest Ann. Thorac. Surg., May 1, 2004; 77(5): 1684 - 1689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Frost, G. J. Nystrom, and C. H. Lang Epinephrine stimulates IL-6 expression in skeletal muscle and C2C12 myoblasts: role of c-Jun NH2-terminal kinase and histone deacetylase activity Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E809 - E817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Anselmi, A. Abbate, F. Girola, G. Nasso, G. G.L. Biondi-Zoccai, G. Possati, and M. Gaudino Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence Eur. J. Cardiothorac. Surg., March 1, 2004; 25(3): 304 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kuramochi, C. C. Lim, X. Guo, W. S. Colucci, R. Liao, and D. B. Sawyer Myocyte contractile activity modulates norepinephrine cytotoxicity and survival effects of neuregulin-1{beta} Am J Physiol Cell Physiol, February 1, 2004; 286(2): C222 - C229. [Abstract] [Full Text]
|
|
|
|
|
|
M. O. Boluyt, A. M. Loyd, M. H. Roth, M. J. Randall, and E. Y. M. Song Activation of JNK in rat heart by exercise: effect of training Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2639 - H2647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. El-Armouche, O. Zolk, T. Rau, and T. Eschenhagen Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure Cardiovasc Res, December 1, 2003; 60(3): 478 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Qin, J. Shite, and C.-s. Liang Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H822 - H832. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||