Kurzfassung

Statins are a well-established family of drugs that lower the cholesterol level and are therefore widely used to reduce atherogenesis and cardiovascular morbidity. Statins competitively inhibit the endoplasmatic reticulum residing enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR). HMGCR converts HMG-CoA to mevalonate and catalyzes the rate-limiting step in cholesterol biosynthesis (Goldstein and Brown, 1990).
During recent years, statins have also been shown to exert...Statins are a well-established family of drugs that lower the cholesterol level and are therefore widely used to reduce atherogenesis and cardiovascular morbidity. Statins competitively inhibit the endoplasmatic reticulum residing enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR). HMGCR converts HMG-CoA to mevalonate and catalyzes the rate-limiting step in cholesterol biosynthesis (Goldstein and Brown, 1990).
During recent years, statins have also been shown to exert pleiotropic immunomodulatory effects that might be of therapeutic benefit in autoimmune disorders. In particular statins were shown to ameliorate the clinical signs of experimental autoimmune encephalomyelitis (EAE), the prototypical animal model of multiple sclerosis (MS)(Youssef et al., 2002). EAE is driven by a proinflammatory T cell response that involves type 1 T-helper (Th1) and the IL-17 producing Th17 cells and is pathologically characterized by demyelination and axonal damage (Zamvil and Steinman, 1990; Komiyama et al., 2006). EAE is induced by active immunization of animals with myelin antigens or by passive transfer of myelin-specific T cells. Although the initial step in EAE is the activation of peripheral T cells various cell types including CNS resident cells such as oligodendrocytes, microglia
and astrocytes participate in disease induction and progression. Disruption of the gene for HMGCR results in early embryonic lethality. Null embryos could be recovered at the blastocysts stage but not later, indicating that loss of the HMG-CoA reductase activity in the germ line leads either to implantation failure or to embryonic death prior to implantation (Ohashi et al., 2003). To overcome the lethal phenotype of the hmgcr deficient mice, we recently generated mice in which the catalytic domain containing exon 15 of the hmgcr gene is flanked by LoxP sites (HMGCRfl/fl mice). This genetic modification allows tissue-specific deletion of the catalytic domain of HMGCR. By breeding this strain to transgenic mouse lines expressing the Cre-recombinase, we will be able to inhibit the mevalonate pathway in a tissue and cell-type specific manner. Thus we will be able to further elucidate
the molecular and cellular mechanisms leading to the improved clinical outcome observed in EAE and MS patients treated with statins. » weiterlesen» einklappen