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Elevated levels of serum homocysteine (Hcy) resulting in hyperhomocysteinemia (HHcy) have been implicated in cardiac pathological conditions including: coronary heart disease (CHD), acute myocardial infarction, arrhythmogenesis and sudden cardiac death (SCD). The mechanisms by which HHcy leads to arrhythmogenesis and SCD are unknown. Novel findings indicate that Hcy is an agonist of the N-methyl-D-aspartate receptor (NMDA-R), known to be present in cardiac tissue, and when activated, increases intracellular calcium leading to increased cell excitability. Also, HHcy induces oxidative stress in cardiac cells and activates matrix metalloproteinases (MMPs) that degrade cell membranes and proteins. Here we review the literature relevant to HHcy-induced oxidative stress leading to cardiac tissue remodelling that may adversely affect cell-to-cell impulse conduction, in particular on the heart's specialized conduction system, and may provide substrate for arrhythmogenesis and SCD. Efficacy of B vitamin supplementation in patient populations with HHcy and CHD is also reviewed.

Background Excessive complement activation is an integral part of ischemia and reperfusion (IR) injury (IRI) of organs. In kidney transplantation the pathological consequence of IRI and complement activation can lead to delayed graft function which in turn is associated with acute rejection. Previous strategies to reduce complement induced IRI required systemic administration of agents, which can lead to increased susceptibility to infections/immune diseases. The objective of this study was to determine whether an increase in complement control defenses of rat kidney endothelium reduces IRI. We hypothesized that increased complement control on the endothelial barrier reduces IR-mediated complement activation and reduces kidney dysfunction. Materials and methods Fisher 344 rats underwent left kidney ischemia for 45 min. and treatment with a novel fusogenic lipid vesicle (FLVs) delivery system to decorate endothelial cells with Vaccinia virus complement control protein (VCP), followed by reperfusion for 24h. Assessment included renal function by serum creatinine and urea, myeloperoxidase assay for neutrophil infiltration, histopathology, and quantification of C3 production in kidneys. Results Animals in which the kidney endothelium was bolstered by FLVs+VCP treatment had better renal function with a significant reduction in serum creatinine as compared to vehicle controls. C3 production was significantly reduced (p<0.05) in treated animals compared to vehicle controls. Conclusion Increasing complement control at the endothelial barrier with FLVs+VCP modulates complement activation/production during the first 24h, reducing renal dysfunction following IRI.

Background Ischemia/reperfusion (IR) injury is an unavoidable consequence of tissue transplantation or replantation that often leads to inflammation and cell death. Excessive complement activation following IR induces endothelial cell injury, altering vascular and endothelial barrier function causing tissue dysfunction. To mitigate the IR response, various systemic anti-complement therapies have been tried. Recently, we developed a localized therapy that uses biotinylated fusogenic lipid vesicles (BioFLVs) to first incorporate biotin tethers onto cell membranes, which are then used to bind therapeutic fusion proteins containing streptavidin (SA) resulting in the decoration of cell membranes. The therapy is applied in two steps using solutions delivered intra-arterially. Materials and methods Alteration of formulation, concentration and duration of incubation of BioFLVs were conducted to demonstrate the ability of the system to modulate biotin tether incorporation in cultured cells. Using a rat hind limb model, the ability of BioFLVs to decorated endothelium of femoral vessels with FITC-labeled SA for 48 h of reperfusion was demonstrated. The feasibility of a BioFLV-based anti-complement therapy was tested in cultured cells using SA fused with vaccinia virus complement control protein (SA-VCP), a C3 convertase inhibitor. Human ovarian carcinoma (SKOV-3) cells were incubated with BioFLVs first and then with SA-VCP. To activate complement the cells were treated with a SKOV-3-specific antibody (trastuzumab) and incubated in human serum. Results Decoration of cells with SA-VCP effectively reduced complement deposition. Conclusions We conclude that BioFLV-mediated decoration of cell membranes with anti-complement proteins reduces complement activation and deposition in vitro and has the potential for application against inappropropriate complement activation in vivo.