Yu Yang, Ohmori Koji, Chen Yan, Sato Chubun, Kiyomoto Hideyasu, Shinomiya Kaori, Takeuchi Hiroto, Mizushige Katsufumi, Kohno Masakazu
Second Department of Internal Medicine, Kagawa University School of Medicine, Kita-gun, Japan.
J Am Coll Cardiol. 2004 Aug 18;44(4):904-13. doi: 10.1016/j.jacc.2004.04.050.
We examined the effects of early treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on the progression of glucose intolerance and cardiovascular remodeling in a model of spontaneously developing type II diabetes mellitus (DM), the Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
Clinical trials showed that pravastatin prevented new-onset DM in hypercholesterolemic patients, and that it was effective in prevention of cardiovascular events in diabetics.
The OLETF rats were treated with pravastatin (100 mg/kg/day) from 5 weeks of age and compared with age-matched untreated OLETF rats and normal Long-Evans Tokushima Otsuka (LETO) rats on serial oral glucose tolerance tests (OGTT) and Doppler echocardiography and on histopathological/biochemical analyses of the heart at 30 weeks.
The OGTT revealed that 40% and 89% of untreated OLETF rats were diabetic at 20 and 30 weeks, respectively, but 0% and only 30%, respectively, were diabetic in the treated OLETF. Left ventricular diastolic function was found impaired from 20 weeks in untreated OLETF but remained normal in the treated-OLETF. The wall-to-lumen ratio and perivascular fibrosis of coronary arteries were increased in untreated-OLETF but were limited in the treated-OLETF at 30 weeks. Moreover, cardiac expressions of a fibrogenic growth factor, transforming growth factor-beta1 (TGF-beta1), and a proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), were increased in untreated-OLETF. However, in the treated-OLETF, overexpressions of TGF-beta1 and MCP-1 were attenuated, which was associated with overexpression of endothelial nitric oxide synthase (eNOS) (2.5-fold of control LETO).
Early pravastatin treatment prevented cardiovascular remodeling in the spontaneous DM model by retarding the progression of glucose intolerance, overexpressing cardiac eNOS, and inhibiting overexpressions of fibrogenic/proinflammatory cytokines.
我们在自发性II型糖尿病（DM）模型——大冢长- Evans 德岛肥胖（OLETF）大鼠中，研究了用3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂普伐他汀进行早期治疗对糖耐量异常进展和心血管重塑的影响。
临床试验表明，普伐他汀可预防高胆固醇血症患者新发DM，且对预防糖尿病患者心血管事件有效。
OLETF大鼠从5周龄开始用普伐他汀（100mg/kg/天）治疗，并与年龄匹配的未治疗OLETF大鼠和正常的大冢长- Evans 德岛（LETO）大鼠进行比较，在30周时进行系列口服葡萄糖耐量试验（OGTT）、多普勒超声心动图检查以及心脏的组织病理学/生化分析。
OGTT显示，未治疗的OLETF大鼠在20周和30周时分别有40%和89%患糖尿病，但治疗组OLETF大鼠在相应时间点患糖尿病的比例分别为0%和仅30%。未治疗的OLETF大鼠从20周起左心室舒张功能受损，但治疗组OLETF大鼠的左心室舒张功能仍保持正常。未治疗的OLETF大鼠在30周时冠状动脉的壁腔比和血管周围纤维化增加，但治疗组OLETF大鼠的上述变化受到限制。此外，未治疗的OLETF大鼠中促纤维化生长因子转化生长因子-β1（TGF-β1）和促炎趋化因子单核细胞趋化蛋白-1（MCP-1）的心脏表达增加。然而，在治疗组OLETF大鼠中，TGF-β1和MCP-1的过表达减弱，这与内皮型一氧化氮合酶（eNOS）的过表达（对照LETO的2.5倍）有关。
早期普伐他汀治疗通过延缓糖耐量异常进展、使心脏eNOS过表达以及抑制促纤维化/促炎细胞因子的过表达，预防了自发性DM模型中的心血管重塑。
