Levrand Sandra, Pacher Pal, Pesse Benoît, Rolli Joelle, Feihl François, Waeber Bernard, Liaudet Lucas
Department of Intensive Care Medicine, University Hospital Center, 1011 Lausanne, Switzerland.
Biochem Biophys Res Commun. 2007 Aug 3;359(3):445-50. doi: 10.1016/j.bbrc.2007.05.147. Epub 2007 May 30.
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.
同型半胱氨酸（HCY）对血管具有毒性，但HCY对心脏的潜在直接毒性尚不清楚。我们通过将H9C2心肌细胞暴露于HCY（0.1 - 5 mM）长达6小时来解决这个问题。在这些浓度下，HCY降低了细胞活力，诱导了坏死和凋亡，并引发了半胱天冬酶 - 3和聚（ADP - 核糖）聚合酶（PARP）的裂解。这与强效氧化剂过氧亚硝酸盐的细胞内生成有关。通过分解催化剂FeTPPS去除过氧亚硝酸盐可显著减少乳酸脱氢酶释放、DNA片段化、半胱天冬酶 - 3和PARP的裂解，并恢复正常细胞形态。在原代大鼠心室心肌细胞中进行的额外实验中，HCY（1 mM，6小时）激活了丝裂原活化蛋白激酶ERK和JNK的磷酸化，这两种是调节心肌细胞凋亡、肥大和重塑的重要应激信号激酶。这些结果首次证明HCY通过过氧亚硝酸盐的生成杀死心肌细胞，并可激活心肌中的关键信号级联反应。
