Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders.
Mitochondrial disorder is characteristic of many myocardial injuries such as endotoxemia, shock, acidosis, ischemia/reperfusion, and others. The goal of possible therapy is to increase ATP production. Derivatives of vitamins K may be a potent electron carrier between various mitochondrial electron-donating and electron-accepting enzyme complexes. We aimed to test the possibility that menadione or its water-soluble derivative AK-135, the newly synthesized analogues of vitamin K1--N-derivatives of 2-methyl-3-aminomethyl 1.4-naphthoquinone, would reduce cardiomyocyte damage after hypoxia or mitochondrial respiratory chain inhibition in culture. Menadione, and more effectively, AK-135, restored the electron flow in defective respiratory chain (hypoxia or rotenone) systems. As was shown in this study, 3 microM of AK-135 restored ATP production after blockade of electron flow through mitochondrial complex I with 5 microM rotenone up to 13.18+/-1.56 vs. 3.21+/-1.12 nmol/mg protein in cells treated with rotenone only. In cultures pretreated with 4 microM dicumarol (DT-diaphorase inhibitor), the protective effect of AK-135 and menadione was abolished completely (1.67+/-1.43 and 2.97+/-0.57 nmol/mg protein, respectively). Inhibition of mitochondrial oxidative phosphorylation caused an increase in intracellular Ca(2+) levels. Here we have demonstrated restoration of calcium oscillations and cardiomyocyte contractility by menadione and its derivative after blockade of NADH: ubiquinone oxidoreductase with rotenone, and decrease of Ca(2+) overloading during hypoxia.
Shneyvays
Vladimir
V
Gonda (Goldschmied) Medical Diagnostic Research Center, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Leshem
Dorit
D
Shmist
Yelena
Y
Zinman
Tova
T
Shainberg
Asher
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D024483:Vitamin K 3 / Q000031:analogs & derivatives / Q000494:pharmacology*
D009285:Naphthoquinones; D014475:Uncoupling Agents; D012402:Rotenone; C053314:AK 135; D024483:Vitamin K 3; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D002118:Calcium