Novel Therapy for Protection against Diabetes and its Complications in Ischemic Heart Disease

摘要 该计划的总体目标是开发和商业化一种新颖，安全，有效的， 糖尿病性心血管疾病（dCVD）的治疗。全球糖尿病患病率从108 人口从1980年的2.5亿增加到2014年的4.22亿，预计到2045年将增加到7亿。百分之九十的 糖尿病患者患有2型糖尿病（T2D），35%的T2D患者患有心功能障碍。那些 2型糖尿病患者发生dCVD的可能性高2 - 3倍。高血糖引起的心血管并发症， 特别是心肌梗死和心力衰竭，是T2D相关发病率和死亡率的主要原因， 占所有糖尿病死亡的68%。 诺和美泰已开发出安全、一流的口服药物，具有预防dCVD的潜力， 通过激活AMPK，抑制mTOR，预防和治疗， 激活炎性小体，抑制IL-11的分泌。因此，我们试图证明， Novomeirs的主要化合物（NMLC）在糖尿病小鼠中具有心脏保护作用， 缺血/再灌注（I/R）损伤后的心肌梗死。NMLC是一种变构AMPK激动剂， mTORC1的独立特异性抑制剂和IL-11分泌抑制剂，其预防 在小鼠TAC模型中，并且在小鼠肝和肺纤维化模型中减少纤维化和炎症。NMLC 应该通过以下方式减少/逆转dCVD中的疾病进展：1）通过以下方式改善脂质和葡萄糖稳态： 激活AMPK; 2）减少氧化应激，抑制ROS的产生，并通过 抑制NLRP 3炎性体和激活AMPK;和3）提供针对I/R的心脏保护 通过激活AMPK和独立地抑制mTOR而损伤，和4）通过 抑制IL-11和mTOR以及激活AMPK。Das博士和Salloum博士（VCU）最近测试了NMLC 在糖尿病小鼠和分离的糖尿病小鼠成年心室心肌细胞中。NMLC改善代谢 糖尿病小鼠和受保护的心肌细胞（分离自糖尿病小鼠）中的参数 缺血/再氧合（SI/RO）损伤。 由于这种药物在糖尿病条件下保护心脏免受I/R损伤的独特潜力，我们 本研究提出以下具体目标：1）在体外证实NMLC的心肌保护机制， IL-11在心脏成纤维细胞中的表达，评估SI/RO模型中人心肌细胞中AMPK/mTOR信号传导 在高血糖下，并扩大NMLC用于体内研究; 2）检查NMLC对心脏代谢的影响， 2型糖尿病小鼠模型，确定NMLC对代谢和糖尿病诱导的心脏变化的影响。 功能，并确认NMLC在体内的心脏保护机制;以及3）确定 在db/db小鼠心肌梗死后，测定NMLC对心肌梗死的影响， 结论：NMLC对缺血再灌注损伤后心肌纤维化有明显的保护作用，并证实了NMLC对缺血后心肌的保护机制。

Abstract The overall goal of this program is the development and commercialization of a novel, safe, and effective therapy for diabetic cardiovascular disease (dCVD). The worldwide prevalence of diabetes has risen from 108 million in 1980 to 422 million in 2014 and is expected to increase to 700 million by 2045. Ninety percent of those with diabetes have type 2 diabetes (T2D), and 35% of those with T2D have cardiac dysfunction. Those with T2D are 2-3 times more likely to develop dCVD. Cardiovascular complications due to hyperglycemia, especially myocardial infarction and heart failure, are the leading cause of T2D-related morbidity and mortality, accounting for 68% of all diabetic deaths. NovoMedix has developed safe, first-in-class, oral drugs that have the potential to prevent dCVD and significantly improve long term outcomes for those with T2D by activating AMPK, inhibiting mTOR, preventing activation of the inflammasome, and inhibiting secretion of IL-11. We, therefore, seek to demonstrate that Novomedix’s leading compound (NMLC) is cardioprotective in diabetic mice and provides protection against myocardial infarction following ischemia/reperfusion (I/R) injury. NMLC is an allosteric AMPK agonist, an independent specific inhibitor of mTORC1 and an inhibitor of IL-11 secretion that prevents heart failure in a mouse TAC model and decreases fibrosis and inflammation in liver and lung fibrosis models in mice. NMLC should reduce/reverse disease progression in dCVD by: 1) improving lipid and glucose homeostasis by activating AMPK; 2) reducing oxidative stress, inhibiting the production of ROS, and reducing inflammation by inhibition of the NLRP3 inflammasome and activation of AMPK; and 3) providing cardioprotection against I/R injury by activating AMPK and independently inhibiting mTOR, and 4) preventing post-I/R cardiac fibrosis by inhibition of IL-11 and mTOR and activation of AMPK. Dr. Das and Dr. Salloum (VCU) recently tested NMLC in diabetic mice and in isolated diabetic mouse adult ventricular cardiomyocytes. NMLC improved metabolic parameters in diabetic mice and protected cardiomyocytes (isolated from diabetic mice) following simulated ischemia/reoxygenation (SI/RO) injury. As a result of the unique potential of this drug to protect the heart against I/R injury in diabetic condition, we propose the following specific aims: 1) confirm NMLC mechanism of cardioprotection in vitro, assess inhibition of IL-11 in cardiac fibroblasts, assess AMPK/mTOR signaling in human cardiomyocytes in an SI/RO model with high glucose, and scale up NMLC for in vivo studies; 2) examine the cardiometabolic impact of NMLC in a mouse model of T2D, determine the effect of NMLC on metabolism and diabetes-induced changes in cardiac function, and confirm mechanism of cardioprotection of NMLC in vivo; and 3) determine the beneficial effect of NMLC in the post-myocardial infarction in db/db mice, determine the effect of NMLC on myocardial infarct and fibrosis after I/R injury, and confirm mechanism of cardioprotection of NMLC in the post-ischemic heart.