Modified Low-Dose Triiodo-L-thyronine Therapy Safely Improves Function Following Myocardial Ischemia-Reperfusion Injury.
Modified Low-Dose Triiodo-L-thyronine Therapy Safely Improves Function Following Myocardial Ischemia-Reperfusion Injury.
复制标题
DOI：
10.3389/fphys.2017.00225
复制
发表时间：
2017
影响因子：
4
通讯作者：
Gerdes AM
中科院分区：
文献类型：
--
作者：
Rajagopalan V;Zhang Y;Pol C;Costello C;Seitter S;Lehto A;Savinova OV;Chen YF;Gerdes AM
背景：我们已经证明，甲状腺激素(TH)具有心脏保护作用，可作为治疗糖尿病心肌病和永久性心肌梗死的安全药物。然而，目前尚无可靠的、临床可翻译的治疗心肌缺血再灌注损伤的方案。我们假设改良的小剂量三碘-L-甲状腺原氨酸(T3)疗法将对IR损伤提供安全的治疗益处。方法：成年雌性大鼠左冠状动脉结扎60min或假手术。在手术和T3治疗(如下所述)后2个月，对大鼠进行功能、形态和分子检查。结果：大鼠手术后给予T3(8μg/kg/d)或自由饮水给药，连续2个月。口服T3显著改善左心室(LV)收缩、松弛和松弛时间常数，并降低β-肌球蛋白重链基因的表达。由于大鼠术后大约6小时才开始饮水，我们随后调查了在再灌流时立即开始改进的T3剂量是否提供了进一步的改善。再灌流后给予小剂量T3(12μg/kg)和小剂量口服T3(4.5μg/kg/d)，连续2个月。与单独口服T3相比，持续的T3治疗(丸剂+小剂量口服)可增强左室收缩能力。与车辆相比，松弛参数也得到了改善。重要的是，这些都是在肥厚、血清游离T3水平或血压没有显著增加的情况下完成的。结论：这是第一项利用商业上可获得的廉价T3为心肌IR提供安全的心脏治疗窗口和优化的、临床可翻译的治疗监测方案的研究。小剂量口服T3辅以再灌流时开始的团注治疗更安全有效。
Background: We have shown that thyroid hormones (THs) are cardioprotective and can be potentially used as safe therapeutic agents for diabetic cardiomyopathy and permanent infarction. However, no reliable, clinically translatable protocol exists for TH treatment of myocardial ischemia-reperfusion (IR) injury. We hypothesized that modified low-dose triiodo-L-thyronine (T3) therapy would confer safe therapeutic benefits against IR injury. Methods: Adult female rats underwent left coronary artery ligation for 60 min or sham surgeries. At 2 months following surgery and T3 treatment (described below), the rats were subjected to functional, morphological, and molecular examination. Results: Following surgery, the rats were treated with T3 (8 μg/kg/day) or vehicle in drinking water ad libitum following IR for 2 months. Oral T3 significantly improved left ventricular (LV) contractility, relaxation, and relaxation time constant, and decreased beta-myosin heavy chain gene expression. As it takes rats ~6 h post-surgery to begin drinking water, we then investigated whether modified T3 dosing initiated immediately upon reperfusion confers additional improvement. We injected an intraperitoneal bolus of T3 (12 μg/kg) upon reperfusion, along with low-dose oral T3 (4.5 μg/kg/day) in drinking water for 2 months. Continuous T3 therapy (bolus + low-dose oral) enhanced LV contractility compared with oral T3 alone. Relaxation parameters were also improved compared to vehicle. Importantly, these were accomplished without significant increases in hypertrophy, serum free T3 levels, or blood pressure. Conclusions: This is the first study to provide a safe cardiac therapeutic window and optimized, clinically translatable treatment-monitoring protocol for myocardial IR using commercially available and inexpensive T3. Low-dose oral T3 therapy supplemented with bolus treatment initiated upon reperfusion is safer and more efficacious.