This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo.

In-stent restenosis results exclusively from neointimal hyperplasia due to mechanical injury and a foreign body response to the prosthesis. Inflammation mediated by monocyte chemoattractant protein-1 (MCP-1) might therefore underlie in-stent restenosis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an Nterminal deletion mutant of the MCP-1 gene into skeletal muscles. We used this strategy to investigate the role of MCP-1 in experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys. Transfection of the mutant MCP-1 gene suppressed monocyte infiltration/activation in the stented arterial wall and markedly reduced the development of neointimal hyperplasia. This strategy also suppressed local expression of MCP-1 and inflammatory cytokines. Therefore, inhibition of MCP-1-mediated inflammation is effective in reducing experimental in-stent restenosis. This strategy might be a useful form of gene therapy against human in-stent restenosis.

Abstract:A variety of neoplastic and non-neoplastic lesions in F344/DuCrj rats, which were used as control animals in chronic toxicity and carcinogenicity studies conducted at the Biosafety Research Center, Foods, Drugs and Pesticides over a 9 year period, are described. The causes of death of animals which were found dead or that were killed in a moribund condition, as well as age-associated differences in the incidence rate of various lesions at 31, 57, 83, and 109 weeks, were also analyzed. The average number of naturally-occurring tumors per rat was 1.68 in male and 0.92 in female rats. The incidence rate of malignant tumors in all animals was 12.5% in male and 11.4% in female rats. The most common tumors were leukemia and benign tumors of the endocrine and reproductive organs. As for the non neoplastic lesions, chronic nephropathy occurred more frequently in male than in female rats. Other lesions commonly observed were atrophic changes in the thymus and reproductive organs, deposits of hemosiderin or ceroid-like materials in a variety of organs, proliferative or hyperplastic changes of the bile ducts, endocrine and reproductive organs, microgranuloma, angiectasis and dilated or cystic changes in a variety of organs, fatty change in the liver and adrenals, and hepatodiaphragmatic nodules of the liver. Nearly all of the above findings increased in both incidence and severity with age. (J Toxicol Pathol 4: 1.24, 1991)