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(Circulation Research. 2003;92:136.)
© 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

Andrea Remondino, Susan H. Kwon, Catherine Communal, David R. Pimentel, Douglas B. Sawyer, Krishna Singh, Wilson S. Colucci

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).

View larger version (18K): [in this window] [in a new window]   Figure 1. A, Inhibitors of ßAR-stimulated apoptosis in ARVMs. Myocytes were exposed to 10 µmol/L norepinephrine and 100 nmol/L prazosin (NE/PZ) for 24 hours, and apoptosis was assessed by TUNEL staining. Under control conditions, 4% to 7% of ARVMs were TUNEL-positive. NE/PZ increased the frequency of apoptotic ARVMs by 3.6±0.2-fold (P<0.0001 vs Control). ßAR-stimulated apoptosis was inhibited by the SOD/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 µmol/L) and Euk-134 (Euk; 50 µmol/L), the mitochondrial permeability transition pore inhibitor bongkrekic acid (BA; 50 µmol/L) and the caspase inhibitor zVAD-fmk (zVAD; 25 µmol/L). The data are from 35 experiments for NE/PZ and 5 to 8 experiments for each inhibitor. *P<0.01 vs NE/PZ; **P<0.001 vs NE/PZ. B, Effect of infection with an adenovirus expressing catalase on ßAR-stimulated apoptosis. Data are from 6 experiments. *P<0.001 vs Lac-Z; 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; P<0.05 vs NE/PZ.

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).

View larger version (17K): [in this window] [in a new window]   Figure 2. A, ßAR-stimulated activation of JNK. ARVMs were exposed to NE/PZ for 15 minutes and phospho-JNK was determined by Western blotting. ßAR stimulation increased JNK activation 2.3±0.4-fold, and this effect was prevented by the SOD/catalase mimetic MnTMPyP (10 µmol/L). Data are from 3 experiments. *P<0.05 vs Control; P<0.01 vs NE/PZ. B, Prevention of ßAR-stimulated apoptosis by the JNK inhibitor SP600125. ARVMs pretreated with SP600125 for 30 minutes were exposed to NE/PZ for 24 hours, and apoptosis was assessed by TUNEL staining. Data are from 8 experiments. *P<0.001 vs Control; P<0.001 vs NE/PZ. C, Effect of infection with an adenovirus expressing a dominant-negative JNK on ßAR-stimulated apoptosis. Data are from 4 experiments. *P<0.001 vs Lac-Z; P<0.001 vs NE/PZ+Lac-Z.

Discussion

We^1,2 and others^3–5 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.

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