Upregulation of myocardial 11S-activated proteasome in experimental hyperglycemia.
This study examined the hypothesis that the ubiquitin proteasome system (UPS) degrades proteins damaged by exposure to hyperglycemia. Experimental hyperglycemia was induced in male rats by treatment with streptozotocin. After 30 days, echocardiography confirmed the presence of cardiomyopathy as ejection fraction, fractional shortening, and diastolic function (E/A ratio) were decreased, and chamber diameter was increased in hyperglycemic animals. Proteasome non-ATP-dependent chymotryptic activity was increased over 2-fold in hyperglycemic hearts, but the ATP-dependent activity was decreased and levels of ubiquitinated proteins were increased. Protein levels of the PA28alpha of the 11S-activator ring were increased by 128% and the PA28beta subunit increased by 58% in the hyperglycemic hearts. The alpha3 subunit of the 20S-proteasome was increased by 82% while the catalytic beta5 subunit was increased by 68% in hyperglycemic hearts. Protein oxidation as indicated by protein carbonyls was significantly higher in hyperglycemic hearts. These studies support the conclusion that the UPS becomes dysfunctional during long term hyperglycemia. However, 11S-activated proteasome was increased suggesting a response to oxidative protein damage and a potential role for this form of the proteasome in a cardiac pathophysiology.
Powell
Saul R
SR
Department of Medicine, The Feinstein Institute for Medical Research and the Albert Einstein College of Medicine, New Hyde Park, NY, USA.
Samuel
Samson Mathews
SM
Wang
Ping
P
Divald
Andras
A
Thirunavukkarasu
Mahesh
M
Koneru
Srikanth
S
Wang
Xuejun
X
Maulik
Nilanjana
N
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000503:physiopathology; D006943:Hyperglycemia / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D013311:Streptozocin; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex