Rydgren Tobias, Sandler Stellan
Department of Medical Cell Biology, Uppsala University, Husargatan 3, P.O. Box 571, Biomedicum, SE-75123 Uppsala, Sweden.
Biochem Biophys Res Commun. 2009 Feb 20;379(4):1076-9. doi: 10.1016/j.bbrc.2009.01.017. Epub 2009 Jan 14.
Besides a cholesterol-lowering effect, simvastatin possesses anti-inflammatory properties attributed to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and/or direct binding to, and inhibition of, the integrin lymphocyte function associated antigen-1 (LFA-1). We have shown that simvastatin protects against multiple low dose streptozotocin (MLDS) induced type 1 diabetes in mice. Presently, we examined if this effect could be abolished by co-administration of mevalonic acid, thus determining if the protective effect is dependent or independent of inhibition of HMG-CoA reductase. Mevalonic acid did not affect the protective effect of simvastatin against MLDS diabetes. Moreover, spleens from these mice did not show any signs of toxic side-effects, thus excluding the possibility that the protective effect is secondary to a general inflammatory response. We suggest that simvastatin's protective effect mainly is independent of HMG-CoA reductase inhibition. This implies that inhibition of LFA-1 activation is important for the protective effect exerted by simvastatin.
除了具有降低胆固醇的作用外，辛伐他汀还具有抗炎特性，这归因于其对3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制作用和/或与整合素淋巴细胞功能相关抗原-1（LFA-1）的直接结合及抑制作用。我们已经表明，辛伐他汀可预防小鼠中多次低剂量链脲佐菌素（MLDS）诱导的1型糖尿病。目前，我们研究了同时给予甲羟戊酸是否会消除这种作用，从而确定这种保护作用是否依赖于对HMG-CoA还原酶的抑制。甲羟戊酸并未影响辛伐他汀对MLDS糖尿病的保护作用。此外，这些小鼠的脾脏未显示出任何毒性副作用的迹象，因此排除了保护作用继发于一般炎症反应的可能性。我们认为，辛伐他汀的保护作用主要独立于对HMG-CoA还原酶 的抑制。这意味着抑制LFA-1激活对于辛伐他汀发挥的保护作用很重要。
