Differential regulation of proteasome function in isoproterenol-induced cardiac hypertrophy.
BACKGROUND
Proteasomal degradation is altered in many disease phenotypes including cardiac hypertrophy, a prevalent condition leading to heart failure. Our recent investigations identified heterogeneous subpopulations of proteasome complexes in the heart and implicated multiple mechanisms for their regulation.


OBJECTIVE
The study aimed at identification of molecular mechanisms changing proteasome function in the hypertrophic heart.


RESULTS
Proteasome function, expression, and assembly were analyzed during the development of cardiac hypertrophy induced by β-adrenergic stimulation. The analysis revealed, for the first time, divergent regulation of proteasome function in cardiac hypertrophy. Proteasome complexes have 3 different proteolytic activities, which are ATP-dependent for 26S complexes (19S assembled with 20S) and ATP-independent for 20S core particles. The 26S activities were enhanced in hypertrophic hearts, partially because of increased expression and assembly of 19S subunits with 20S core complexes. In contrast, caspase- and trypsin-like 20S activities were significantly decreased. Activation of endogenous cAMP-dependent protein kinase (PKA) rescued the depressed 20S functions, supporting the notion that PKA signaling is a positive regulator of protein degradation in the heart. Chymotrypsin-like 20S activity was stably maintained during cardiac remodeling, indicating a switch in proteasome subpopulations, which was supported by altered expression and incorporation of inducible β subunits.


CONCLUSIONS
Three novel mechanisms for the regulation of proteasome activities were discovered in the development of cardiac hypertrophy: (1) increased incorporation of inducible subunits in 20S proteasomes; (2) enhanced 20S sensitivity to PKA activation; and (3) increased 26S assembly. PKA modulation of proteasome complexes may provide a novel therapeutic avenue for restoration of cardiac function in the diseased myocardium.
Drews
Oliver
O
School of Medicine, University of California-Los Angeles, 675 Charles E Young Drive, Los Angeles, CA 90095-1760, USA.
Tsukamoto
Osamu
O
Liem
David
D
Streicher
John
J
Wang
Yibin
Y
Ping
Peipei
P
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006868:Hydrolysis; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011489:Protein Denaturation / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D017868:Cyclic AMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex; D007545:Isoproterenol
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