| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 UMDNJ - New Jersey Medical School
2 NJIT
3 UMDNJ - Robert Wood Johnson Medical School
4 University of Medicine and Dentistry of New Jersey, New Jersey Medical School
* To whom correspondence should be addressed. E-mail: deprech{at}umdnj.edu.
We tested the possibility that proteasome inhibition may reverse pre-existing cardiac hypertrophy and improve remodeling upon pressure overload. Mice were submitted to aortic banding, and followed up for three weeks. The proteasome inhibitor epoxomicin (0.5 mg/kg) or the vehicle were injected daily, starting two weeks after banding. At the end of the third week, vehicle-treated banded animals showed significant (P<0.05) increase in proteasome activity (PA), left ventricle/tibial length (LV/TL), myocyte cross-sectional area (MCA) and myocyte apoptosis compared to sham, and developed signs of heart failure, including increased lung weight/TL and decreased ejection fraction. Compared to that group, banded mice treated with epoxomicin showed no increase in PA, a lower LV/TL and MCA, reduced apoptosis, stabilized ejection fraction, and no signs of heart failure. Because overload-mediated cardiac remodeling largely depends on the activation of the proteasome-regulated transcription factor NF-
B, we tested whether epoxomicin would prevent this activation. NF-B activity increased significantly upon overload, which was suppressed by epoxomicin. The expression of NF-B-dependent transcripts, encoding collagen types I and III and the matrix metalloprotease MMP-2, increased (P<0.05) after banding, which was abolished by epoxomicin. Accumulation of collagen after overload, as measured by histology, was 75% lower (P<0.05) with epoxomicin compared to vehicle. Myocyte apoptosis increased by 4-fold in hearts submitted to aortic banding as compared to sham, which was reduced by half upon epoxomicin treatment. Therefore, we propose that proteasome inhibition after the onset of pressure overload rescues ventricular remodeling by stabilizing cardiac function, by suppressing further progression of hypertrophy, by repressing collagen accumulation, and by reducing myocyte apoptosis.
This article has been cited by other articles:
|
|
 |
|
  X. Yu and D. C. Kem Proteasome inhibition during myocardial infarction Cardiovasc Res, October 4, 2009; (2009) cvp309v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Su and X. Wang The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective Cardiovasc Res, September 16, 2009; (2009) cvp287v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Tsukamoto, T. Minamino, and M. Kitakaze Functional alterations of cardiac proteasomes under physiological and pathological conditions Cardiovasc Res, September 4, 2009; (2009) cvp282v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Carrier, S. Schlossarek, M. S. Willis, and T. Eschenhagen Ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy Cardiovasc Res, August 10, 2009; (2009) cvp247v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hedhli and C. Depre Proteasome inhibitors and cardiac cell growth Cardiovasc Res, August 7, 2009; (2009) cvp226v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Luo, J. Wong, and B. Wong Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy Cardiovasc Res, August 6, 2009; (2009) cvp225v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Vignier, S. Schlossarek, B. Fraysse, G. Mearini, E. Kramer, H. Pointu, N. Mougenot, J. Guiard, R. Reimer, H. Hohenberg, et al. Nonsense-Mediated mRNA Decay and Ubiquitin-Proteasome System Regulate Cardiac Myosin-Binding Protein C Mutant Levels in Cardiomyopathic Mice Circ. Res., July 31, 2009; 105(3): 239 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kloss, S. Meiners, A. Ludwig, and B. Dahlmann Multiple cardiac proteasome subtypes differ in their susceptibility to proteasome inhibitors Cardiovasc Res, July 31, 2009; (2009) cvp217v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dreger, K. Westphal, A. Weller, G. Baumann, V. Stangl, S. Meiners, and K. Stangl Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection Cardiovasc Res, July 15, 2009; 83(2): 354 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Sui, D. Li, H. Qiu, V. Gaussin, and C. Depre Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival Circ. Res., April 10, 2009; 104(7): 887 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liu, H. Zheng, M. Tang, Y.-C. Ryu, and X. Wang A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2541 - H2550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Friehs Proteasome inhibition in hypertrophied myocardium Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1373 - H1374. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
