Wang Rui, Xi Lei, Kukreja Rakesh C
Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University. Richmond, Virginia.
Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University. Richmond, Virginia
J Pharmacol Exp Ther. 2017 Apr;361(1):29-38. doi: 10.1124/jpet.116.239087. Epub 2017 Jan 25.
Diabetes is associated with a high risk for ischemic heart disease. We have previously shown that phosphodiesterase 5 inhibitor tadalafil (TAD) induces cardioprotection against ischemia/ reperfusion (I/R) injury in diabetic mice. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug that has been reported to reduce hyperglycemia in diabetic patients. Therefore, we hypothesized that a combination of TAD and HCQ may induce synergistic cardioprotection in diabetes. We also investigated the role of insulin-Akt-mammalian target of rapamycin (mTOR) signaling, which regulates protein synthesis and cell survival. Adult male db/db mice were randomized to receive vehicle, TAD (6 mg/kg), HCQ (50 mg/kg), or TAD + HCQ daily by gastric gavage for 7 days. Hearts were isolated and subjected to 30-minute global ischemia, followed by 1-hour reperfusion in Langendorff mode. Cardiac function and myocardial infarct size were determined. Plasma glucose, insulin and lipid levels, and relevant pancreatic and cardiac protein markers were measured. Treatment with TAD + HCQ reduced myocardial infarct size (17.4% ± 4.3% vs. 37.8% ± 4.9% in control group, < 0.05) and enhanced the production of ATP. The TAD + HCQ combination treatment also reduced fasting blood glucose, plasma free fatty acids, and triglyceride levels. Furthermore, TAD + HCQ increased plasma insulin levels (513 ± 73 vs. 232 ± 30 mU/liter, < 0.05) with improved insulin sensitivity, larger pancreatic -cell area, and pancreas mass. Insulin-like growth factor-1 (IGF-1) levels were also elevated by TAD + HCQ (343 ± 14 vs. 262 ± 22 ng/ml, < 0.05). The increased insulin/IGF-1 resulted in activation of downstream Akt/mTOR cellular survival pathway. These results suggest that combination treatment with TAD and HCQ could be a novel and readily translational pharmacotherapy for reducing cardiovascular risk factors and protecting against myocardial I/R injury in type 2 diabetes.
糖尿病与缺血性心脏病的高风险相关。我们之前已经表明,磷酸二酯酶5抑制剂他达拉非(TAD)可诱导对糖尿病小鼠缺血/再灌注(I/R)损伤的心脏保护作用。羟氯喹(HCQ)是一种广泛使用的抗疟疾和抗炎药物,据报道可降低糖尿病患者的高血糖。因此,我们假设TAD和HCQ联合使用可能在糖尿病中诱导协同的心脏保护作用。我们还研究了胰岛素-Akt-雷帕霉素哺乳动物靶蛋白(mTOR)信号传导的作用,该信号传导调节蛋白质合成和细胞存活。成年雄性db/db小鼠被随机分为通过胃管饲法每日接受载体、TAD(6毫克/千克)、HCQ(50毫克/千克)或TAD+HCQ,持续7天。分离心脏并在Langendorff模式下进行30分钟的全心缺血,随后进行1小时的再灌注。测定心脏功能和心肌梗死面积。测量血浆葡萄糖、胰岛素和脂质水平以及相关的胰腺和心脏蛋白标志物。TAD+HCQ治疗可减小心肌梗死面积(对照组为37.8%±4.9%,TAD+HCQ组为17.4%±4.3%,P<0.05)并增强ATP的产生。TAD+HCQ联合治疗还降低了空腹血糖、血浆游离脂肪酸和甘油三酯水平。此外,TAD+HCQ增加了血浆胰岛素水平(513±73对232±30毫单位/升,P<0.05),改善了胰岛素敏感性,增大了胰腺β细胞面积和胰腺质量。TAD+HCQ还提高了胰岛素样生长因子-1(IGF-1)水平(343±14对262±22纳克/毫升,P<0.05)。胰岛素/IGF-1的增加导致下游Akt/mTOR细胞存活途径的激活。这些结果表明,TAD和HCQ联合治疗可能是一种新型且易于转化的药物疗法,用于降低2型糖尿病患者的心血管危险因素并预防心肌I/R损伤。