A theory for the mechanism of homocysteine-induced vascular pathogenesis

An attempt is made to reveal the mechanism of homocysteine-induced vascular pathogenesis and a theory is developed on the basis of an analysis of available data. In the blood, homocysteine molecules, which possess the capacity of forming chelate complexes with metallic cations including calcium ions, interact with the calcium ions of the calcium-dependent cell adhesions/junctions of the vascular endothelium. Such an action results in the departure of calcium ions from some cell adhesions/junctions, causing the latter structures to dissociate and the vascular endothelium to be injured. While such factors as high levels of plasma calcium ion tend to restore the disrupted cell adhesions/junctions, other factors including blood pressure, bloodstream shearing force and high cholesterol/phospholipid ratio in the membranes are unfavorable to the repair. The injuries to the vascular endothelium may initiate inflammatory reactions. Over a long time, as such endothelial injuries occur repeatedly and, additionally, a small number of unrepaired cell adhesion/junction disruptions exacerbate slowly but progressively, inflammation may be constantly present. As the inflammation becomes excessive or uncontrollable, irreversible vascular pathogenesis takes place. Added to the condition is thrombosis caused by excessive coagulation activities triggered by the vascular endothelium injuries. In addition to the interference due to decreased membrane fluidity to the restoration of interrupted cell adhesions/junctions, cholesterol may further promote vascular pathogenesis (induced by either homocysteine or other factors) by impeding the detachment and departure of the foam cells from the vascular lesions. Such impediment is presumably related to an inhibitory effect on cell shape change and cell movement by the formation of a stable and rigid cytoskeleton-membrane network characterized by reduced membrane malleability and enhanced cytoskeleton-membrane association.