LIPID-LOWERING BY DIET REDUCES MATRIX METALLOPROTEINASE ACTIVITY AND INCREASES COLLAGEN CONTENT OF RABBIT ATHEROMA - A POTENTIAL MECHANISM OF LESION STABILIZATION

Background-Proteolytic enzyme activity in lipid-rich atheroma may prom ote plaque rupture and precipitate acute coronary syndromes, This stud y tested the hypothesis that lipid lowering stabilizes plaques by redu cing proteolytic activity. Methods and Results-We produced experimenta l atheroma in 33 rabbits by balloon injury and an atherogenic diet (0. 3% cholesterol and 4.7% coconut oil) for 4 months. At that time, 15 ra bbits were killed (baseline group). The remaining animals were divided into two groups: a hyperlipemic group continued to consume a choleste rol-enriched diet (0.05% to 0.2%) for 16 more months (n=5) and a lipid -lowering group consumed a purified chow diet with no added cholestero l or fat for 8 (n=3) or 16 months (n=10), Macrophage accumulation and interstitial collagenase (matrix metalloproteinase-1, MMP-1) expressio n in the lesion were measured by quantitative image analysis of standa rdized sections of immunostained aortas, Baseline lesions expressed hi gh levels of MMP-1 and contained many macrophages. These features of p laque instability persisted in the hyperlipemic group, However, the li pid-lowering group showed progressive reduction in both macrophage con tent and MMP-1 immunoreactivity with time. Aortic rings of the baselin e and hyperlipemic groups elaborated gelatinolytic, caseinolytic, and elastinolytic activity attributable to MMP-2, MMP-3, or MMP-9, monitor ed by SDS-PAGE zymography, Proteolytic activity decreased markedly in the lipid-lowering group. Aortic content of interstitial collagen, det ermined by sirius red staining, increased in the lipid-lowering group compared with the baseline or continued hyperlipemic groups, indicatin g that lipid lowering reinforced the fibrous skeleton of the atheroma. Conclusions-These results establish a mechanism by which lipid loweri ng may stabilize vulnerable plaques by reduced expression and activity of enzymes that degrade the arterial extracellular matrix and render atheroma less susceptible to disruption and thrombosis by favoring col lagen accumulation in the fibrous cap.