Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats.
Diabetes and oxidative stress concur to cardiac myocyte death in various experimental settings. We assessed whether N-acetyl-L-cysteine (NAC), an antioxidant and glutathione precursor, has a protective role in a rat model of streptozotocin (STZ)-induced diabetes and in isolated myocytes exposed to high glucose (HG). Diabetic rats were treated with NAC (0.5 g/kg per day) or vehicle for 3 months. At sacrifice left ventricle (LV) myocyte number and size, collagen deposition and reactive oxygen species (ROS) were measured by quantitative histological methods. Diabetes reduced LV myocyte number by 29% and increased myocyte volume by 20% compared to non-diabetic controls. NAC protected from myocyte loss (+25% vs. untreated diabetics, P < 0.05) and reduced reactive hypertrophy (-16% vs. untreated diabetics, P < 0.05). Perivascular fibrosis was high in diabetic rats (+88% vs. control, P < 0.001) but prevented by NAC. ROS production and fraction of ROS-positive cardiomyocyte nuclei were drastically raised in diabetic rats (2.4- and 5.1-fold vs. control, P < 0.001) and normalized by NAC. In separate experiments, isolated adult rat ventricular myocytes were incubated in a medium containing high concentrations of glucose (HG, 25 mM) +/- 0.01 mM NAC; myocyte survival (Trypan blue exclusion and apoptosis by TUNEL) and glutathione content were evaluated. The number of dead and apoptotic myocytes increased five and 6.7-fold in HG and glutathione decreased by 48% (P < 0.05). NAC normalized cell death and apoptosis and prevented glutathione loss. NAC effectively protects from hyperglycemia-induced myocyte cell death and compensatory hypertrophy through direct scavenging of ROS and replenishment of the intracellular glutathione content.
Fiordaliso
Fabio
F
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy. fiordaliso@marionegri.it
Bianchi
Roberto
R
Staszewsky
Lidia
L
Cuccovillo
Ivan
I
Doni
Mirko
M
Laragione
Teresa
T
Salio
Monica
M
Savino
Costanza
C
Melucci
Silvia
S
Santangelo
Francesco
F
Scanziani
Eugenio
E
Masson
Serge
S
Ghezzi
Pietro
P
Latini
Roberto
R
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D006332:Cardiomegaly / Q000517:prevention & control; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D005978:Glutathione; D005947:Glucose; D000111:Acetylcysteine