Vitamin c inhibits hypoxia-induced damage and apoptotic signaling pathways in cardiomyocytes and ischemic hearts

• Published in: Free radical biology & medicine Vol. 37; no. 9; pp. 1419 - 1429
• Main Authors: Guaiquil, Victor H., Golde, David W., Beckles, Daniel L., Mascareno, Eduardo J., Siddiqui, M.A.Q.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2004
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Ascorbic acid; Ascorbic Acid - pharmacology; Cell Hypoxia - drug effects; Dehydroascorbic acid; Dehydroascorbic Acid - metabolism; Disease Models, Animal; Free radicals; Heart - drug effects; Heart - physiology; Hypoxia; Hypoxia - prevention & control; Ischemia; Jak/STAT; Muscle Cells - cytology; Muscle Cells - drug effects; Muscle Cells - physiology; Myocardial Ischemia - pathology; Myocardial Ischemia - prevention & control; Myocardium - cytology; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; AA; Reactive oxygen species; Ascorbic acid; Free radicals; HPLC-ECD; CK; Jak/STAT; DAPI; Signaling; STAT; Dehydroascorbic acid; TUNEL; Ischemia; Jak; ROS; DCF-DA; Hypoxia; DHA; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2004.06.041

Reactive oxygen species play a central role in myocardial ischemic injury and are a target for therapeutic intervention. Vitamin C is an essential antioxidant yet difficult to deliver in pharmacologic concentration to the myocardium. We found that adult rat cardiomyocytes accumulate vitamin C by transporting dehydroascorbic acid (DHA), the oxidized form of vitamin C, but do not transport ascorbic acid. Loading cells with vitamin C by DHA treatment resulted in resistance to hypoxia- and hypoxia/reoxygenation-induced cell death associated with the quenching of reactive oxygen species. When rats were injected with DHA before coronary occlusion, the ascorbic acid content in the heart was six to eight times higher than in untreated controls and myocardial infarction was reduced by 62%. DHA also provided significant protection when administered intravenously 2 h after coronary occlusion. In cardiomyocytes subjected to hypoxia/reoxygenation, DHA treatment resulted in decreased apoptosis associated with inhibition of Bax expression, caspase-3 activation, and cytochrome c translocation into the cytoplasm. DHA treatment also inhibited Jak2, STAT1, and STAT5 phosphorylation, and increased STAT3 phosphorylation, in hypoxic cardiomyocytes and ischemic myocardial tissue. Our findings suggest that DHA may be useful as a cardioprotectant in ischemic heart disease.