cytochrome-c-t and Hypercholesterolemia

Ischemic postcontioning (IPoC) is an effective method to prevent myocardial ischemia reperfusion injury (MIRI), but its cardioprotection is usually blocked in the presence of hypercholesterolemia (HC) and the potential mechanism is still unknown. In this study, we investigated the roles of reperfusion injury salvage kinase (RISK) and apoptosis-related pathways in the attenuation of cardioprotection of IPoC in the presence of HC. The results showed that IPoC significantly decreased the infarct size and apoptosis, improved the recovery of ischemic myocardium, but these beneficial effects were reversed by high cholesterol diet-induced HC. Moreover, we also found that HC inhibited the phosphorylation of Akt and ERK1/2 which usually activated by IPoC in normal heart, induced excessive apoptosis by down-regulating Bcl-2 and up-regulating Bax, cytochrome c, caspase 9 and caspase 3 when compared with that in normal heart. Taken together, our results demonstrated that the cardioprotection of IPoC was abolished by HC, which was associated with inactivation of RISK signal pathway and dysregulation of downstream apoptosis-related pathway.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Coronary Vessels; Cytochromes c; Heart; Hypercholesterolemia; Ischemic Postconditioning; Lipids; Male; Mitogen-Activated Protein Kinase 3; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction

Trans-2, 4-dimethoxystibene (S3) is a synthetic stilbenes. In the present study, S3 was investigated to assess its neuroprotective effect against the toxicity induced by Abeta(25-35) in hypercholesterolemic rats. Rats were fed with hypercholesterolemic chow for six weeks, and then received a single intracerebroventricular (i.c.v.) injection of Abeta(25-35) and a treatment with S3 or estradiol (E2). Behavioral changes and neuron apoptosis in rats were evaluated using Morris water maze, step-down test and TUNEL tests. To further explore the mechanism of S3, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), choline acetyl transferase (ChAT), acetylcholine esterase (AchE) and the contents of malondialdehyde (MDA) in hippocampus were analyzed by spectrophotometric method. At the same time, the releases of cytochrome C were analyzed by Western Blot, and the contents of acetylcholine (Ach) were analyzed by Elisa. The data showed that consumption of S3 (50mg/kg/d) significantly ameliorated the cognitive deficits and neuron apoptosis caused by i.c.v. injection of Abeta(25-35). Meanwhile, S3 reversed the decreased activity of ChAT, SOD, GSH-Px and contents of Ach, as well as the increased activity of AchE, MDA contents and the release of cytochrome C in hippocampus. These findings suggest that S3 may be a potential candidate for development as therapeutic agent to treat AD through regulating cholinergic nerve system and anti-oxidative mechanism.

Topics: Acetylcholine; Acetylcholinesterase; Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; Choline O-Acetyltransferase; Cognition Disorders; Cytochromes c; Disease Models, Animal; Female; Glutathione Peroxidase; GPI-Linked Proteins; Hippocampus; Hypercholesterolemia; Injections, Intraventricular; Malondialdehyde; Maze Learning; Neurons; Neuroprotective Agents; Peptide Fragments; Psychomotor Performance; Rats; Rats, Wistar; Reaction Time; Stilbenes; Superoxide Dismutase; Time Factors

Although hypercholesterolemia is known to impair endothelium-dependent vasodilation (EDV) long before the appearance of atherosclerotic plaques, it remains unclear whether the immune mechanisms that have been implicated in atherogenesis also contribute to the early oxidative stress and endothelial cell dysfunction elicited by hypercholesterolemia. EDV (wire myography), superoxide generation (cytochrome c reduction), and NAD(P)H oxidase mRNA expression were monitored in aortic rings from wild-type (WT) and mutant mice placed on either a normal diet or a cholesterol-enriched diet (HC) for 2 wk. WT mice on HC exhibited impaired EDV, enhanced superoxide generation, and increased expression of NAD(P)H oxidase subunit Nox-2 mRNA. The impaired EDV and increased superoxide generation induced by HC were significantly blunted in severe combined immunodeficient (SCID) mice and CD4+ T lymphocyte-deficient mice. These responses were also attenuated in HC mice genetically deficient in IFN-gamma; however, adoptive transfer of WT-HC CD4+ T lymphocytes to IFN-gamma-deficient recipients restored HC-induced responses. The HC-induced impaired EDV and oxidative stress were also attenuated in HC mice genetically deficient in Nox-2 (gp91(phox-/-)) and in WT-->gp91(phox-/-)-HC chimeras. HC-induced gp91(phox) mRNA expression was significantly blunted in mice deficient in CD4+ T cells or IFN-gamma and was restored with adoptive transfer of WT-HC CD4+ T cells to IFN-gamma-deficient recipients. These findings implicate the immune system in the early endothelial cell dysfunction associated with hypercholesterolemia and are consistent with a mechanism of impaired EDV that is mediated by CD4+ T cells and IFN-gamma, acting through the generation of superoxide from vascular NAD(P)H oxidase.

Topics: Acetylcholine; Adoptive Transfer; Animals; B-Lymphocytes; CD4 Antigens; CD4-Positive T-Lymphocytes; Cytochromes c; Disease Models, Animal; DNA-Activated Protein Kinase; DNA-Binding Proteins; Endothelium, Vascular; Hypercholesterolemia; Interferon-gamma; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Myography; NADPH Oxidase 2; NADPH Oxidases; Nuclear Proteins; Oxidative Stress; RNA, Messenger; Superoxides; Vasodilation; Vasodilator Agents