Proteasome inhibition improves diaphragm function in congestive heart failure rats.
In congestive heart failure (CHF), diaphragm weakness is known to occur and is associated with myosin loss and activation of the ubiquitin-proteasome pathway. The effect of modulating proteasome activity on myosin loss and diaphragm function is unknown. The present study investigated the effect of in vivo proteasome inhibition on myosin loss and diaphragm function in CHF rats. Coronary artery ligation was used as an animal model for CHF. Sham-operated rats served as controls. Animals were treated with the proteasome inhibitor bortezomib (intravenously) or received saline (0.9%) injections. Force generating capacity, cross-bridge cycling kinetics, and myosin content were measured in diaphragm single fibers. Proteasome activity, caspase-3 activity, and MuRF-1 and MAFbx mRNA levels were determined in diaphragm homogenates. Proteasome activities in the diaphragm were significantly reduced by bortezomib. Bortezomib treatment significantly improved diaphragm single fiber force generating capacity (approximately 30-40%) and cross-bridge cycling kinetics (approximately 20%) in CHF. Myosin content was approximately 30% higher in diaphragm fibers from bortezomib-treated CHF rats than saline. Caspase-3 activity was decreased in diaphragm homogenates from bortezomib-treated rats. CHF increased MuRF-1 and MAFbx mRNA expression in the diaphragm, and bortezomib treatment diminished this rise. The present study demonstrates that treatment with a clinically used proteasome inhibitor improves diaphragm function by restoring myosin content in CHF.
van Hees
Hieronymus W H
HW
Deptartment of Pulmonary Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands. H.vanhees@long.umcn.nl
Li
Yi-Ping
YP
Ottenheijm
Coen A C
CA
Jin
Bingwen
B
Pigmans
Cindy J C
CJ
Linkels
Marianne
M
Dekhuijzen
P N Richard
PN
Heunks
Leo M A
LM
D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D018995:Myosin Heavy Chains / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D054875:Ubiquitination
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D053148:Caspase 3; D018995:Myosin Heavy Chains; D009218:Myosins