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Resolution of Apoptosis in Atherosclerotic Plaque by Dietary Modification and Statin Therapy

¹ School of Medicine Hannover, Hannover, Germany
² Division of Cardiology, University of California, Irvine, Irvine, California
³ Cardiovascular Pathology, Gaithersburg, Maryland
⁴ University Hospital Maastricht, Maastricht, The Netherlands

Although apoptosis within atherosclerotic plaques is associated with plaque vulnerability and rupture, the role of inhibition of the apoptotic process is not clear. We evaluated the impact of dietary modification and statin therapy (measures known to favorably influence outcomes in coronary disease) on the incidence of apoptosis in experimental atherosclerotic lesions. Methods: A total of 30 animals were studied; 1 group of 6 animals served as the controls (group 1), and the remaining 24 animals were subjected to balloon de-endothelialization of the abdominal aorta and a high-cholesterol diet. These atherosclerotic animals were randomized as follows: high-cholesterol diet for 4 mo (n = 6; untreated atherosclerotic group [group 2]), high-cholesterol diet for 3 mo and normal chow diet for 1 mo (n = 6; diet withdrawal group [group 3]), and high-cholesterol diet for 4 mo and simvastatin orally every day of the last month (n = 6; statin therapy group [group 4]). ^99mTc-Annexin A5 was used for noninvasive detection of apoptosis in groups 1–4. The remaining 6 rabbits on a high-cholesterol diet for 4 mo were studied with radiolabeled mutant annexin A5 (n = 6; nonspecific control group [group 5]). Quantitative annexin A5 uptake in the abdominal aorta was determined and compared with the histologic and immunohistochemical characteristics of the atherosclerotic lesions. Results: Maximum annexin A5 uptake (mean ± SD, 0.051 ± 0.009 percentage injected dose per gram [%ID/g] of tissue) was observed in the untreated atherosclerotic animals. The uptake was substantially reduced in the diet withdrawal (0.03 ± 0.006 %ID/g; P < 0.0001) and statin therapy (0.03 ± 0.006 %ID/g; P < 0.0001) groups. The plaques in the untreated high-cholesterol group demonstrated advanced atherosclerotic lesions. On the other hand, the diet withdrawal and statin therapy groups showed histologic characteristics of stabilization, including the resolution of macrophage infiltration and an increase in smooth muscle cell content. There was a marked reduction in the apoptosis of macrophages. No significant uptake of annexin A5 or mutant annexin A5 was seen in rabbits on the normal chow diet or atherosclerotic rabbits, respectively. Conclusion: Dietary modification and statin therapy in atherosclerosis lead to a reduction in apoptosis and contribute to plaque stabilization. It can be hypothesized that a reduction in apoptosis is a favorable process in atherosclerotic disease.

Key Words: programmed cell death • atheroma • 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

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