Hypercholesterolemia causes mechanical weakening of rabbit atheroma - Local collagen loss as a prerequisite of plaque rupture

Hypercholesterolemia may render atherosclerotic plaques prone to rupture. T o test this hypothesis, catheters with matrix-covered balloons were implant ed into the aorta of rabbits fed standard or 0.5% cholesterol chow (n=70). In 1 month, fibrous plaques developed around the balloon. Time-dependent ac cumulation of cholesteryl esters and free cholesterol was detected in the p laques of the cholesterol-fed group only. The pressure needed to rupture th e plaque by balloon inflation was used as an index of plaque strength. Thre e months after the catheter implantation, the breaking pressure was 2.1 tim es lower (P<0.05) in cholesterol-fed rabbits. It was accompanied by collage n loss, as measured by plaque hydroxyproline content, but not with deficien cy of collagen cross-linking. Sirius red staining showed preservation of co llagen originally covering the balloon and accumulation of nascent collagen in the lesions of standard chow-fed rabbits. In the cholesterol-fed group, both mature and new collagen underwent degradation predominantly in the pl aque shoulders. Collagen breakdown was associated with local accumulation o f foamy macrophages. Gel zymography demonstrated relative enhancement of ge latinolytic activity at 92 and 72 kDa, as well as caseinolytic activity at 57, 45, and 19 kDa in the lipid-laden plaques. Lipid accumulation in the pl aque was also associated with a loss of smooth muscle cells, the cellular s ource of the collagen fibers. The remaining smooth muscle cells showed incr eased collagen synthesis, although it was insufficient to counterbalance co llagen degradation and cell loss. Thus, we have obtained direct evidence th at hypercholesterolemia is accompanied by enhanced local collagen degradati on, which is potentially responsible for plaque weakening.