Proteasome activation during cardiac hypertrophy by the chaperone H11 Kinase/Hsp22.
OBJECTIVE
The regulation of protein degradation by the proteasome during cardiac hypertrophy remains largely unknown. Also, the proteasome translocates to the nuclear periphery in response to cellular stress in yeast, which remains unexplored in mammals. The purpose of this study was to determine the quantitative and qualitative adaptation of the proteasome during stable cardiac hypertrophy.


RESULTS
We measured proteasome activity, expression and sub-cellular distribution in a model of chronic cardiac hypertrophy induced by the stress-response chaperone H11 Kinase/Hsp22 (Hsp22). Over-expression of Hsp22 in a transgenic (TG) mouse leads to a 30% increase in myocyte cross-sectional area compared to wild-type (WT) mice (P < 0.01). Characterization of the proteasome in hearts from TG mice vs. WT revealed an increased expression of both 19S and 20S subunits (P < 0.05), a doubling in 20S catalytic activity (P < 0.01), a redistribution of both subunits from the cytosol to the nuclear periphery, and a four-fold increase in nuclear-associated 20S catalytic activity (P < 0.001). The perinuclear proteasome co-localized and interacted with Hsp22. Inhibition of proteasome activity by epoxomicin reduced hypertrophy in TG by 50% (P < 0.05). Adeno-mediated over-expression of Hsp22 in isolated cardiac myocytes increased both cell growth and proteasome activity, and both were prevented upon inhibition of the proteasome. Similarly, stimulation of cardiac cell growth by pro-hypertrophic stimuli increased Hsp22 expression and proteasome activity, and proteasome inhibition in that setting prevented hypertrophy. Proteasome inhibitors also prevented the increase in rate of protein synthesis observed after over-expression of Hsp22 or upon addition of pro-hypertrophic stimuli.


CONCLUSIONS
Hsp22-mediated cardiac hypertrophy promotes an increased expression and activity, and a subcellular redistribution of the proteasome. Inhibition of the proteasome reverses cardiac hypertrophy upon Hsp22 over-expression or upon stimulation by pro-hypertrophic hormones, and also blocks the stimulation of protein synthesis in these conditions.
Hedhli
Nadia
N
New Jersey Medical School, Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, MSB G-609, Newark, NJ 07103, USA.
Wang
Li
L
Wang
Qian
Q
Rashed
Eman
E
Tian
Yimin
Y
Sui
Xiangzhen
X
Madura
Kiran
K
Depre
Christophe
C
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology* / Q000517:prevention & control; D049109:Cell Proliferation; D004789:Enzyme Activation; D050886:HSP20 Heat-Shock Proteins / Q000502:physiology*; D006360:Heat-Shock Proteins; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors
D050886:HSP20 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C490206:Hspb8 protein, mouse; D018832:Molecular Chaperones; D009124:Muscle Proteins; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex