Allicin protects against myocardial apoptosis and fibrosis in streptozotocin-induced diabetic rats.
To evaluate the cardioprotective effect of allicin (AL) on myocardial injury of streptozotocin (STZ)-induced diabetic rats and to further explore its underlying mechanisms. Hyperglycemia was induced in rats by single intraperitoneal injection of STZ (40 mg/kg). Three days after STZ induction, the hyperglycemic rats (plasma glucose levels ≥ 16.7 mmol/l) were treated with AL by intraperitoneal injection at the doses of 4 mg/kg, 8 mg/kg, and 16 mg/kg daily for 28 days. The fasting blood glucose levels were measured on every 7th day during the 28 days of treatment. The body weight, blood glucose, and parameter of cardiac function were detected after 4 weeks to study the cardioprotective effects of AL on diabetic rats in vivo. The apoptotic index of cardiomyocytes was estimated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The expressions of Fas, Bcl-2, CTGF, and TGF-β(1) protein were studied by immunohistochemistry. Laser scanning confocal microscopy technique was utilized to observe the effects of AL on intracellular calcium concentration ([Ca(2+)](i)) in rat ventricular cardiomyocytes. AL at the doses of 4 mg/kg, 8 mg/kg, and 16 mg/kg significantly reduced blood glucose levels in a dose-dependent manner and increased body weight as well compared with the model group. Hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/dtmax and -dp/dtmax) were significantly restored back to normal levels in AL-treated (8 mg/kg and 16 mg/kg) rats compared with diabetic model rats. AL markedly inhibited cardiomyocyte apoptosis induced by diabetic cardiac injury. Further investigation revealed that this inhibitory effect on cell apoptosis was mediated by increasing anti-apoptotic protein Bcl-2 and decreasing pro-apoptotic protein Fas. Additional experiments demonstrated AL abrogated myocardial fibrosis by blocking the expressions of CTGF and TGF-β(1) protein. AL shows protective action on myocardial injury in diabetic rats. The possible mechanisms were involved in reducing blood glucose, correcting hemodynamic impairment, reducing Fas expression, activating Bcl-2 expression, decreasing intracellular calcium overload, inhibiting the expressions of TGF-β(1) and CTGF, and further improving cardiac function.
Department of Pharmacology, Harbin Medical University, Daqing 163319, PR China.
Yang
Y
Liu
Hanping
H
Qi
Ye
Y
Wang
Mingli
M
Wu
Yonggang
Y
Cao
Wei
W
Huang
Lei
L
Li
Zhong
Z
Ji
Hongli
H
Sun
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004220:Disulfides; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000633:toxicity; D013441:Sulfinic Acids / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D001786:Blood Glucose; C526316:CCN2 protein, rat; D002316:Cardiotonic Agents; D004220:Disulfides; C491898:Fas protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D013441:Sulfinic Acids; D016212:Transforming Growth Factor beta; D019014:fas Receptor; D055513:Connective Tissue Growth Factor; C006452:allicin; D013311:Streptozocin; D002118:Calcium