© 2000 American Heart Association, Inc.
Cellular Biology |
Cardiomyocyte Apoptosis Induced by G
q Signaling Is Mediated by Permeability Transition Pore Formation and Activation of the Mitochondrial Death Pathway
From the Department of Pharmacology (J.W.A., A.P., C.K.M., J.H.B.), University of California, San Diego, La Jolla, Calif; Idun Pharmaceuticals, Inc (R.C.A.), La Jolla, Calif; and COR Therapeutics, Inc (D.O.), South San Francisco, Calif.
Correspondence to Joan Heller Brown, Department of Pharmacology, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0636. E-mail jhbrown{at}ucsd.edu
Abstract—Expression
of the wild-type 
subunit of Gq stimulates phospholipase C and
induces hypertrophy in cardiomyocytes. Addition of Gq-coupled receptor
agonists additionally activates phospholipase C, as does expression of
a constitutively active mutant form of Gq. Under these conditions,
hypertrophy is rapidly succeeded by apoptotic cellular and molecular
changes, including myofilament disorganization, loss of mitochondrial
membrane potential, alterations in Bcl-2 family protein levels, DNA
fragmentation, increased caspase activity (
4-fold), cytochrome
c redistribution, and nuclear
chromatin condensation in 12% of the cells. We used various
interventions to define the molecular relationships between these
events and identify potential sites at which these features of
apoptosis could be rescued. Treatment with caspase inhibitors prevented
DNA fragmentation and promoted myocyte survival; however, cytochrome
c release and loss of
mitochondrial membrane potential still occurred. In contrast, treatment
with bongkrekic acid, an inhibitor of the mitochondrial permeability
transition pore, not only prevented DNA fragmentation and reduced
nuclear chromatin condensation but also preserved mitochondrial
membrane potential and limited cytochrome
c redistribution to only 2%
of cells. These data demonstrate the central role of mitochondrial
membrane potential in initiation of caspase activation and downstream
apoptotic events and suggest that preservation of mitochondrial
integrity is crucial for prolonging the life and function of
cardiomyocytes exposed to pathological levels of
stress.
Key Words: cardiomyocyte • apoptosis • mitochondria • G proteins
This article has been cited by other articles:
 |
|
 |
|
  A. Diwan, J. Wansapura, F. M. Syed, S. J. Matkovich, J. N. Lorenz, and G. W. Dorn II Nix-Mediated Apoptosis Links Myocardial Fibrosis, Cardiac Remodeling, and Hypertrophy Decompensation Circulation, January 22, 2008; 117(3): 396 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Gustafsson and R. A. Gottlieb Heart mitochondria: gates of life and death Cardiovasc Res, January 15, 2008; 77(2): 334 - 343. [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]
|
|
|
|
 |
|
 C. K. Means, C.-Y. Xiao, Z. Li, T. Zhang, J. H. Omens, I. Ishii, J. Chun, and J. H. Brown Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2944 - H2951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Del Re, S. Miyamoto, and J. H. Brown RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte Apoptosis J. Biol. Chem., March 16, 2007; 282(11): 8069 - 8078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-D. Lee, C.-H. Chu, E.-J. Huang, M.-C. Lu, J.-Y. Liu, C.-J. Liu, H.-H. Hsu, J. A. Lin, W.-W. Kuo, and C.-Y. Huang Roles of insulin-like growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation. Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E306 - E314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Obreztchikova, H. Elouardighi, M. Ho, B. A. Wilson, Z. Gertsberg, and S. F. Steinberg Distinct Signaling Functions for Shc Isoforms in the Heart J. Biol. Chem., July 21, 2006; 281(29): 20197 - 20204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT J. Biol. Chem., November 18, 2005; 280(46): 38505 - 38512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Peavy, K. B. Hubbard, A. Lau, R. B. Fields, K. Xu, C. J. Lee, T. T. Lee, K. Gernert, T. J. Murphy, and J. R. Hepler Differential Effects of Gq{alpha}, G14{alpha}, and G15{alpha} on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles Mol. Pharmacol., June 1, 2005; 67(6): 2102 - 2114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Faadiel Essop and L. H. Opie Metabolic therapy for heart failure Eur. Heart J., October 2, 2004; 25(20): 1765 - 1768. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Onan, L. Pipolo, E. Yang, R. D. Hannan, and W. G. Thomas Urotensin II Promotes Hypertrophy of Cardiac Myocytes via Mitogen-Activated Protein Kinases Mol. Endocrinol., September 1, 2004; 18(9): 2344 - 2354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P.M van Empel and L. J De Windt Myocyte hypertrophy and apoptosis: a balancing act Cardiovasc Res, August 15, 2004; 63(3): 487 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mayorga, N. Bahi, M. Ballester, J. X. Comella, and D. Sanchis Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death J. Biol. Chem., August 13, 2004; 279(33): 34882 - 34889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Zhang, S. Miyamoto, and J. H. Brown Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes? Recent Prog. Horm. Res., January 1, 2004; 59(1): 141 - 168. [Abstract] [Full Text]
|
|
|
|
|
|
K. A. Webster and N. H. Bishopric Apoptosis Inhibitors for Heart Disease Circulation, December 16, 2003; 108(24): 2954 - 2956. [Full Text] [PDF]
|
|
|
|
|
|
Y. Hayakawa, M. Chandra, W. Miao, J. Shirani, J. H. Brown, G. W. Dorn II, R. C. Armstrong, and R. N. Kitsis Inhibition of Cardiac Myocyte Apoptosis Improves Cardiac Function and Abolishes Mortality in the Peripartum Cardiomyopathy of G{alpha}q Transgenic Mice Circulation, December 16, 2003; 108(24): 3036 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Howes, J. F. Arthur, T. Zhang, S. Miyamoto, J. W. Adams, G. W. Dorn II, E. A. Woodcock, and J. H. Brown Akt-mediated Cardiomyocyte Survival Pathways Are Compromised by G{alpha}q-induced Phosphoinositide 4,5-Bisphosphate Depletion J. Biol. Chem., October 10, 2003; 278(41): 40343 - 40351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. Pu, Q. Ma, and S. Izumo NFAT Transcription Factors Are Critical Survival Factors That Inhibit Cardiomyocyte Apoptosis During Phenylephrine Stimulation In Vitro Circ. Res., April 18, 2003; 92(7): 725 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Pang, D. L. Hunton, P. Bounelis, and R. B. Marchase Hyperglycemia Inhibits Capacitative Calcium Entry and Hypertrophy in Neonatal Cardiomyocytes Diabetes, December 1, 2002; 51(12): 3461 - 3467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Sussman, A. McCulloch, and T. K. Borg Dance Band on the Titanic: Biomechanical Signaling in Cardiac Hypertrophy Circ. Res., November 15, 2002; 91(10): 888 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Samarel IGF-1 Overexpression Rescues the Failing Heart Circ. Res., April 5, 2002; 90(6): 631 - 633. [Full Text] [PDF]
|
|
|
|
|
|
K. Takuma, P. Phuagphong, E. Lee, K. Mori, A. Baba, and T. Matsuda Anti-apoptotic Effect of cGMP in Cultured Astrocytes. INHIBITION BY cGMP-DEPENDENT PROTEIN KINASE OF MITOCHONDRIAL PERMEABLE TRANSITION PORE J. Biol. Chem., December 14, 2001; 276(51): 48093 - 48099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ueda, R. Morishita, H. Itoh, S. Narumiya, K. Mikoshiba, K. Kato, and T. Asano Galpha 11 Induces Caspase-mediated Proteolytic Activation of Rho-associated Kinase, ROCK-I, in HeLa Cells J. Biol. Chem., November 2, 2001; 276(45): 42527 - 42533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Xu, Y. Wang, A. Ayub, and M. Ashraf Mitochondrial KATP channel activation reduces anoxic injury by restoring mitochondrial membrane potential Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1295 - H1303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Z. Feuerstein and D. Rozanski G Proteins and Heart Failure : Is G{alpha}q a Novel Target for Heart Failure? Circ. Res., December 8, 2000; 87(12): 1085 - 1086. [Full Text] [PDF]
|
|