Homocysteine induces cell death in H9C2 cardiomyocytes through the generation of peroxynitrite.
Homocysteine (HCY) is toxic on blood vessels, but a potential direct toxicity of HCY on the heart is unknown. We addressed this issue by exposing H9C2 cardiomyocytes to HCY (0.1-5 mM) for up to 6h. At these concentrations, HCY reduced cell viability, induced necrosis and apoptosis and triggered the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). This was associated with the intracellular generation of the potent oxidant peroxynitrite. Removing peroxynitrite by the decomposition catalyst FeTPPS considerably reduced LDH release, DNA fragmentation, cleavage of caspase-3 and PARP, and restored normal cell morphology. In additional experiments performed in primary rat ventricular cardiomyocytes, HCY (1 mM, 6h) activated the phosphorylation of the MAP kinases ERK and JNK, two essential stress signaling kinases regulating myocardial apoptosis, hypertrophy and remodeling. These results provide the first demonstration that HCY kills cardiomyocytes through the generation of peroxynitrite and can activate key signaling cascades in the myocardium.
Levrand
Sandra
S
Department of Intensive Care Medicine, University Hospital Center, 1011 Lausanne, Switzerland.
Pacher
Pal
P
Pesse
Benoît
B
Rolli
Joelle
J
Feihl
François
F
Waeber
Bernard
B
Liaudet
Lucas
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002384:Catalysis; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006711:Homocystine / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D006711:Homocystine; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3