Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya, Turkey.
J Bioenerg Biomembr. 2013 Aug;45(4):343-52. doi: 10.1007/s10863-013-9514-z. Epub 2013 May 3.
In recent years, many findings have been presented about the potential benefit of statin therapy on diabetes-induced cardiovascular complications. Cardioprotective effects of statins were suggested to be mediated at least in part through inhibition of small GTPases, particularly those of the Rho family. The present study was designed to examine whether rosuvastatin can improve electrical remodeling and contractile dysfunction in type 1 diabetic rat heart via modulation of RhoA pathway. Type 1 diabetes was induced by single dose injection of STZ (50 mg/kg). One week after injection rosuvastatin (10 mg/kg/day) and sham treatment was given for 5 weeks in the diabetic rats, as well as in control groups. Shortening and Ca²⁺ transients were recorded in myocytes loaded with Fura2-AM. Membrane currents and Ca²⁺ transients were measured synchronously via whole-cell patch clamping. In untreated diabetic rats, relaxation of shortening and decay of the matched Ca²⁺ transients were prolonged. Fractional shortening and Ca²⁺ transients were also decreased. Rosuvastatin treatment reversed those changes. I(CaL) density did not change in either group but rosuvastatin recovered the loss of sarcoplasmic reticulum Ca²⁺ and Na⁺/Ca²⁺ exchange as evidenced from amplitude and decay of caffeine-induced Ca²⁺ transients, peak INCX and calculated sarcoplasmic reticulum Ca²⁺ content. Diabetes-induced attenuation of I(to) and I(sus) was also reversed, whilst I(K1) was unchanged in diabetes and unaffected by treatment. Rosuvastatin prevented the diabetes-induced increase in RhoA expression. Plasma cholesterol and triglyceride levels were higher in diabetic rats, but rosuvastatin reduced only the latter. In conclusion, HMG-CoA reductase inhibitor rosuvastatin can prevent diabetes-induced electrical and functional remodeling of heart due to inhibition of RhoA signalling rather than reduction of cholesterol level.
近年来，许多研究结果表明他汀类药物治疗对糖尿病引起的心血管并发症具有潜在益处。他汀类药物的心脏保护作用至少部分通过抑制小 GTPases 来介导，特别是 Rho 家族的小 GTPases。本研究旨在探讨瑞舒伐他汀是否可以通过调节 RhoA 通路改善 1 型糖尿病大鼠心脏的电重构和收缩功能障碍。1 型糖尿病通过单次注射 STZ（50mg/kg）诱导。注射后 1 周，在糖尿病大鼠和对照组中给予瑞舒伐他汀（10mg/kg/天）和假处理 5 周。用 Fura2-AM 负载的心肌细胞记录缩短和 Ca²⁺瞬变。通过全细胞膜片钳同步测量膜电流和 Ca²⁺瞬变。在未经治疗的糖尿病大鼠中，缩短的松弛和匹配的 Ca²⁺瞬变的衰减延长。分数缩短和 Ca²⁺瞬变也减少。瑞舒伐他汀治疗逆转了这些变化。在两组中 I（CaL）密度均未改变，但瑞舒伐他汀恢复了肌浆网 Ca²⁺和 Na⁺/Ca²⁺交换的丧失，证据是咖啡因诱导的 Ca²⁺瞬变的幅度和衰减、峰值 INCX 和计算的肌浆网 Ca²⁺含量。糖尿病诱导的 Ito 和 Issus 的衰减也被逆转，而 I（K1）在糖尿病中不变且不受治疗影响。瑞舒伐他汀可预防糖尿病诱导的 RhoA 表达增加。糖尿病大鼠的血浆胆固醇和甘油三酯水平较高，但瑞舒伐他汀仅降低后者。总之，HMG-CoA 还原酶抑制剂瑞舒伐他汀可以通过抑制 RhoA 信号而不是降低胆固醇水平来预防糖尿病引起的心脏电重构和功能重构。
