The ubiquitin-proteasome system contributes to the inflammatory injury in ischemic diabetic myocardium: the role of glycemic control.
BACKGROUND
Because the ubiquitin-proteasome pathway (UPS) is required for activation of nuclear factor kappa beta (NFkB), a transcription factor that regulates inflammatory genes, we evaluated the UPS activity, NFkB activation, and tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, in ischemic specimens of diabetic myocardium and relate them to the glycemic control (HbA(1c)), oxidative stress (nitrotyrosine, a modified amino acid produced by reactive O(2)), and cardiac outcome (echocardiographic parameters). Moreover, the role of UPS, NFkB, and TNF-alpha in the cardiac tissue injury of acute ischemia/reperfusion (I/R) was evaluated in streptozotocin (STZ)-hyperglycemic rats. Finally, this study aimed to elucidate whether an intervention on UPS with bortezomib, an inhibitor of UPS, may counteract the extensive myocardial infarction and increased inflammatory reaction into the hyperglycemic myocardium.


METHODS
Ventricular biopsy specimens from 16 nondiabetic and 18 type 2 diabetic patients presenting with unstable angina who underwent coronary artery bypass were collected during coronary bypass surgery. Ejection fraction (EF); myocardial performance index (MPI), which measures both systolic and diastolic function, immunostaining, and cardiac levels of nitrotyrosine; UPS activity; NFkB; and TNF-alpha were investigated in both ischemic human myocardium and heart tissue from STZ-hyperglycemic rats subject to a myocardial ischemia/reperfusion procedure.


RESULTS
We found that diabetic patients had higher MPI (P<.041) and reduced EF (P<.008) compared with nondiabetic patients. Diabetic specimens had higher nitrotyrosine, UPS activity, NFkB, and TNF-alpha levels compared with nondiabetic patients (P<.001). This was mirrored by consistently high levels of UPS and inflammatory markers in STZ-infarcted hearts, associated with high myocardial damage. In contrast, lesions from normoglycemic animals as well as from hyperglycemic rats treated with bortezomib showed low levels of ubiquitin-proteasome activity, inflammation, and myocardial damage (P<.01).


CONCLUSIONS
By contributing to the increased inflammation, the UPS overactivity may enhance the risk of complication during myocardial ischemia in diabetic patients.
Marfella
Raffaele
R
Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy. raffaele.marfella@unina2.it
Di Filippo
Clara
C
Portoghese
Michele
M
Siniscalchi
Mario
M
Martis
Simone
S
Ferraraccio
Franca
F
Guastafierro
Salvatore
S
Nicoletti
Gianfranco
G
Barbieri
Michelangela
M
Coppola
Antonino
A
Rossi
Francesco
F
Paolisso
Giuseppe
G
D'Amico
Michele
M
D000789:Angina, Unstable / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011480:Protease Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D025801:Ubiquitin
D001897:Boronic Acids; D005609:Free Radicals; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C002744:3-nitrotyrosine; D014443:Tyrosine; D000069286:Bortezomib; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D046988:Proteasome Endopeptidase Complex