on November 10, 2003
Published online before print November 10, 2003, doi: 10.1161/01.CIR.0000096481.45105.13
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 7, 2003
From the Division of Cardiology, University of Texas-Houston Medical School (P.R., S.S., J.Y., H.T.); the Department of Medicine, Baylor College of Medicine (Y.-P.L., M.B.R.); St Luke’s Episcopal Hospital and Texas Heart Institute (H.T.); and the Division of Organ Transplantation, University of Texas-Houston Medical School (S.S.), Houston, Tex. * To whom correspondence should be addressed. E-mail: Heinrich.Taegtmeyer{at}uth.tmc.edu.
Background--Mechanical unloading of the heart results in atrophic remodeling. In skeletal muscle, atrophy is associated with inactivation of the mammalian target of rapamycin (mTOR) pathway and upregulation of critical components of the ubiquitin proteosome proteolytic (UPP) pathway. The hypothesis is that mechanical unloading of the mammalian heart has differential effects on pathways of protein synthesis and degradation. Methods and Results--In a model of atrophic remodeling induced by heterotopic transplantation of the rat heart, we measured gene transcription, protein expression, polyubiquitin content, and regulators of the mTOR pathway at 2, 4, 7, and 28 days. In atrophic hearts, there was an increase in polyubiquitin content that peaked at 7 days and decreased by 28 days. Furthermore, gene and protein expression of UbcH2, a ubiquitin conjugating enzyme, was also increased early in the course of unloading. Transcript levels of TNF- Conclusions--Atrophy of the heart, secondary to mechanical unloading, is associated with early activation of the UPP. The simultaneous activation of the mTOR pathway suggests active remodeling, involving both protein synthesis and degradation.
Revised on July 18, 2003
Accepted on July 22, 2003
Atrophic Remodeling of the Heart In Vivo Simultaneously Activates Pathways of Protein Synthesis and Degradation
Peter Razeghi MD,
, a known regulator of UbcH2-dependent ubiquitin conjugating activity, were upregulated early and transiently in the atrophying rat heart. Unexpectedly, p70S6K and 4EBP1, downstream components of mTOR, were activated in atrophic rat heart. This activation was independent of Akt, a known upstream regulator of mTOR. Rapamycin treatment of the unloaded rat hearts inhibited the activation of p70S6K and 4EBP1 and subsequently augmented atrophy in these hearts compared with vehicle-treated, unloaded hearts.
Key words: genes • remodeling • proteins • mechanics
This article has been cited by other articles:
 |
|
 |
|
  P. C. Schulze Myocardial lipid accumulation and lipotoxicity in heart failure J. Lipid Res., November 1, 2009; 50(11): 2137 - 2138. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kassiotis, K. Ballal, K. Wellnitz, D. Vela, M. Gong, R. Salazar, O. H. Frazier, and H. Taegtmeyer Markers of Autophagy Are Downregulated in Failing Human Heart After Mechanical Unloading Circulation, September 15, 2009; 120(11_suppl_1): S191 - S197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhu, M. H. Soonpaa, H. Chen, W. Shen, R. M. Payne, E. A. Liechty, R. L. Caldwell, W. Shou, and L. J. Field Acute Doxorubicin Cardiotoxicity Is Associated With p53-Induced Inhibition of the Mammalian Target of Rapamycin Pathway Circulation, January 6, 2009; 119(1): 99 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Sharma, P. Dhillon, R. Wambolt, H. Parsons, R. Brownsey, M. F. Allard, and J. H. McNeill Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin-diabetic rat Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1609 - H1620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sharma, P. H. Guthrie, S. S. Chan, S. Haq, and H. Taegtmeyer Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart Cardiovasc Res, October 1, 2007; 76(1): 71 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Herrmann, L. O. Lerman, and A. Lerman Ubiquitin and Ubiquitin-Like Proteins in Protein Regulation Circ. Res., May 11, 2007; 100(9): 1276 - 1291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. F. Petricoin III, V. Espina, R. P. Araujo, B. Midura, C. Yeung, X. Wan, G. S. Eichler, D. J. Johann Jr., S. Qualman, M. Tsokos, et al. Phosphoprotein Pathway Mapping: Akt/Mammalian Target of Rapamycin Activation Is Negatively Associated with Childhood Rhabdomyosarcoma Survival Cancer Res., April 1, 2007; 67(7): 3431 - 3440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Razeghi, M.-E. Wang, K. A. Youker, L. Golfman, S. Stepkowski, and H. Taegtmeyer Lack of NF-{kappa}B1 (p105/p50) attenuates unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression in rodent heart Cardiovasc Res, April 1, 2007; 74(1): 133 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patterson, C. Ike, P. W. Willis IV, G. A. Stouffer, and M. S. Willis The Bitter End: The Ubiquitin-Proteasome System and Cardiac Dysfunction Circulation, March 20, 2007; 115(11): 1456 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Fielitz, E. van Rooij, J. A. Spencer, J. M. Shelton, S. Latif, R. van der Nagel, S. Bezprozvannaya, L. de Windt, J. A. Richardson, R. Bassel-Duby, et al. Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction PNAS, March 13, 2007; 104(11): 4377 - 4382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Adams, A. Linke, U. Wisloff, C. Doring, S. Erbs, N. Krankel, C. C. Witt, S. Labeit, U. Muller-Werdan, G. Schuler, et al. Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility Cardiovasc Res, January 1, 2007; 73(1): 120 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Depre, Q. Wang, L. Yan, N. Hedhli, P. Peter, L. Chen, C. Hong, L. Hittinger, B. Ghaleh, J. Sadoshima, et al. Activation of the Cardiac Proteasome During Pressure Overload Promotes Ventricular Hypertrophy Circulation, October 24, 2006; 114(17): 1821 - 1828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, G. H. Hockerman, H. W. Green III, C. F. Babbs, S. I. Mohammad, D. Gerrard, M. A. Latour, B. London, K. M. Hannon, and A. L. Pond Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway FASEB J, July 1, 2006; 20(9): 1531 - 1533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Razeghi, M. Buksinska-Lisik, N. Palanichamy, S. Stepkowski, O. H. Frazier, and H. Taegtmeyer Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart FASEB J, June 1, 2006; 20(8): 1090 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Razeghi and H. Taegtmeyer Cardiac Remodeling: UPS Lost in Transit Circ. Res., November 11, 2005; 97(10): 964 - 966. [Full Text] [PDF]
|
|
|
|
|
|
N. Hedhli, M. Pelat, and C. Depre Protein turnover in cardiac cell growth and survival Cardiovasc Res, November 1, 2005; 68(2): 186 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Reid Response of the ubiquitin-proteasome pathway to changes in muscle activity Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1423 - R1431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Skurk, Y. Izumiya, H. Maatz, P. Razeghi, I. Shiojima, M. Sandri, K. Sato, L. Zeng, S. Schiekofer, D. Pimentel, et al. The FOXO3a Transcription Factor Regulates Cardiac Myocyte Size Downstream of AKT Signaling J. Biol. Chem., May 27, 2005; 280(21): 20814 - 20823. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Lisy, M. M. Redfield, J. A. Schirger, and J. C. Burnett Jr. Atrial BNP endocrine function during chronic unloading of the normal canine heart Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R158 - R162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. SHARMA, J. V. ADROGUE, L. GOLFMAN, I. URAY, J. LEMM, K. YOUKER, G. P. NOON, O. H FRAZIER, and H. TAEGTMEYER Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart FASEB J, November 1, 2004; 18(14): 1692 - 1700. [Abstract] [Full Text] [PDF]
|
|