High doses of S-methylcysteine cause hypoxia-induced cardiomyocyte apoptosis accompanied by engulfment of mitochondaria by nucleus

• Published in: Biomedicine & pharmacotherapy 2017-10, Vol.94, p.589-597
• Main Authors: El-Magd, Mohammed A., Abdo, Walied S., El-Maddaway, Mustafa, Nasr, Nasr M., Gaber, Rasha A., El-Shetry, Eman S., Saleh, Ayman A., Alzahrani, Faisal Abdulrahman Ali, Abdelhady, Doaa H.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Apoptosis; Apoptosis - drug effects; Biomarkers - metabolism; Cell Hypoxia; Cell Nucleus - metabolism; Cysteine - administration & dosage; Cysteine - analogs & derivatives; Cysteine - isolation & purification; Cysteine - toxicity; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Garlic - chemistry; Hypoxia; Intranuclear mitochondria; Male; Mitochondria - drug effects; Mitochondria - pathology; Myocardium - metabolism; Myocytes, Cardiac - drug effects; Oxidative Stress - drug effects; Rats; Rats, Wistar; ROS; SMC; Superoxide Dismutase - metabolism; Up-Regulation - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2017.07.100

Despite its important role as a medicinal plant, some studies reported a toxic effect for garlic (Allium sativum) when given in higher doses. Herein, we investigated the possible cardiotoxic effects of high doses of S-methylcysteine (SMC), a water soluble organosulfur compound present in garlic. Rats were orally administered SMC at a low dose (50mg), high dose (150mg) and very high dose (300mg)/kg body weight, or saline (control) for 10days. High and very high doses of SMC resulted in a significant increase in serum cardiac injury biomarkers [aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and cardiac troponin T (cTnT)], as well as oxidative stress marker nitric oxide (NO) concentration in heart and a significant decrease in cardiac superoxide dismutase (SOD) activity. Moreover, ultrastructure findings in myocardium of rats treated by high and very high doses showed inter-bundle vacuolation, loss of myofibrils, and centripetal movement of mitochondria towards nucleus. The mitochondria were partially surrounded by nuclear membrane at high dose SMC, and completely engulfed by nucleus at very high dose. This centripetal movement of mitochondria accompanied by cardiomyocytes hypoxia-induced apoptosis as evident by increasing TUNEL positive cells as well as upregulation of apoptotic genes (caspase3 and Bax), hypoxia inducible factor 1 alpha (HIF1α), dynein light chain 1 (DYNLL1) and downregulation of the anti-apoptotic marker, Bcl2. We conclude that high and very high doses of SMC cause hypoxia induced cardiomyocyte apoptosis accompanied by engulfment of mitochondria by nucleus.