s-adenosylhomocysteine and Necrosis

Hyperhomocysteinaemia (HHC) is thought to be a risk factor for cardiovascular disease including heart failure. While numerous studies have analyzed the role of homocysteine (Hcy) in the vasculature, only a few studies investigated the role of Hcy in the heart. Therefore we have analyzed the effects of Hcy on isolated cardiomyocytes.. H9c2 cells (rat cardiomyoblast cells) and adult rat cardiomyocytes were incubated with Hcy and were analyzed for cell viability. Furthermore, we determined the effects of Hcy on intracellular mediators related to cell viability in cardiomyocytes, namely NOX2, reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsi (m)) and ATP concentrations.. We found that incubation of H9c2 cells with 0.1 mM D,L-Hcy (= 60 microM L-Hcy) resulted in an increase of DeltaPsi (m) as well as ATP concentrations. 1.1 mM D,L-Hcy (= 460 microM L-Hcy) induced reversible flip-flop of the plasma membrane phospholipids, but not apoptosis. Incubation with 2.73 mM D,L-Hcy (= 1.18 mM L-Hcy) induced apoptosis and necrosis. This loss of cell viability was accompanied by a thread-to-grain transition of the mitochondrial reticulum, ATP depletion and nuclear NOX2 expression coinciding with ROS production as evident from the presence of nitrotyrosin residues. Notably, only at this concentration we found a significant increase in S-adenosylhomocysteine which is considered the primary culprit in HHC.. We found concentration-dependent effects of Hcy in cardiomyocytes, varying from induction of reversible flip-flop of the plasma membrane phospholipids, to apoptosis and necrosis.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Caspase 3; Cell Membrane; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Gene Expression Regulation; Homocysteine; Membrane Fluidity; Membrane Glycoproteins; Membrane Potential, Mitochondrial; Mitochondria, Heart; Models, Biological; Myocytes, Cardiac; NADPH Oxidase 2; NADPH Oxidases; Necrosis; Phospholipids; Protein Processing, Post-Translational; Rats; S-Adenosylhomocysteine; S-Adenosylmethionine

We investigated the effect of S-adenosyl-L-methionine (SAMe) on the prevention of the delayed neuronal death in rats subjected to transient and brief forebrain ischemia. As the results, SAMe dose-dependently protected the hippocampal CA1 neurons from degeneration and necrosis, whose effect was suppressed by simultaneous administration of S-adenosyl-L-homocysteine, a potent inhibitor in transmethylation. No protective effect was observed in CDP-choline, phosphatidylcholine and L-methionine. Therefore, it is necessary for the prevention of the delayed neuronal death to enhance cerebral SAMe level and to activate transmethylation using SAMe as a methyl donor in postischemic brain.

Topics: Animals; Cell Membrane; Cell Survival; Cytidine Diphosphate Choline; Hippocampus; Ischemic Attack, Transient; Male; Methionine; Methylation; Necrosis; Nerve Degeneration; Neurons; Phosphatidylcholines; Rats; Rats, Inbred Strains; S-Adenosylhomocysteine; S-Adenosylmethionine