Decreased PI3K Signaling and Long QT Syndrome in Diabetes

描述(由申请人提供)： 获得性长QT综合征(LQTS)是一种潜在的致命性心脏疾病，可由药物引起，也与糖尿病有关。糖尿病人群中QT间期延长的发生率高于非糖尿病人群，QT间期延长是糖尿病患者心血管死亡的独立危险因素。最近癌症治疗的一个主要进展是开发了靶向治疗，抑制酪氨酸激酶、磷脂酰肌醇3-激酶(PI3K)和其他在癌症发生中发挥关键作用的信号分子。酪氨酸激酶抑制剂(TKIs)显著提高了慢性粒细胞白血病等癌症患者的生存率，目前正在进行临床试验的几种PI3K抑制剂也显示出良好的抗癌活性。然而，这些药物可能会导致LQTS。我们调查了由这些药物引起的LQTS的起源，并惊讶地发现心脏动作电位时程的延长并不是唯一的原因是复极化钾电流Ikr的减少。相反，正如我们最近在《科学转化医学》上报道的那样，多重电流(Ikr、Iks、ICal和峰值INa)减少，而长时间(持续)钠电流(INAP)增加。TKI通过抑制PI3K信号通路而引起这些效应。众所周知，糖尿病与胰岛素反应组织(包括心脏)中PI3K信号的减少有关。因此，我们的主要假设是，糖尿病患者的低心脏PI3K信号增加了药物诱导的LQTS的风险。我们将使用两个糖尿病小鼠模型的心肌细胞和心脏，以及胰岛素/PI3K信号通路下调的犬心肌细胞来验证这一假设。相反，我们假设胰岛素激活心脏PI3K信号可以改善药物诱导的LQTS。我们建议的研究将确定胰岛素/葡萄糖/钾输注是否能逆转药物诱导的犬体内LQTS。最后，我们假设除了胰岛素受体外，还有多种酪氨酸激酶调节心肌细胞的动作电位。我们将使用药理学和shRNA策略来确定犬心肌细胞中所有通过PI3K发出信号以调节时相的酪氨酸激酶。这种综合的方法将促进更安全的TKI的开发，这些TKI针对参与致癌的特定激酶，同时避免对可能导致LQTS的激酶的影响。我们相信，这些拟议研究的结果将导致开发突破性的预防和治疗策略来对抗这种致命的心脏疾病。

DESCRIPTION (provided by applicant): Acquired long QT syndrome (LQTS) is a potentially lethal cardiac condition that can be caused by medications and is also associated with diabetes mellitus. The prevalence of QT prolongation is higher in the diabetic vs. the non-diabetic population, and QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. A major recent advance in cancer treatment has been the development of targeted therapies that inhibit tyrosine kinases, phosphoinositide 3-kinases (PI3Ks), and other signaling molecules that play critical roles in carcinogenesis. Tyrosine kinase inhibitors (TKIs) have significantly improved patient survival for cancers such as chronic myeloid leukemia, and several PI3K inhibitors now in clinical trials also show promising anti-cancer activity. However, these drugs can cause LQTS. We investigated the origins of the LQTS induced by these drugs and discovered to our surprise that prolongation of the cardiac action potential duration (APD) was not due uniquely to a reduction in the repolarizing potassium current, IKr. Instead, as we recently reported in Science Translational Medicine, multiple currents (IKr, IKs, ICaL, and peak INa) were reduced, while long-lasting (persistent) sodium current (INaP) was increased. TKIs caused these effects by inhibiting PI3K signaling. It is well established that diabetes mellitus is associated with decreased PI3K signaling in insulin- responsive tissues, including the heart. Therefore, our main hypothesis is that low cardiac PI3K signaling in diabetes accentuates the risk of drug-induced LQTS. We will test this hypothesis using myocytes and hearts from two diabetic mouse models, as well as canine myocytes in which the insulin/PI3K signaling pathway is down-regulated. Conversely, we hypothesize that insulin activation of cardiac PI3K signaling ameliorates drug- induced LQTS. Our proposed studies will determine whether insulin/glucose/potassium infusion reverses drug- induced LQTS in vivo in dogs. Lastly, we hypothesize that there are multiple tyrosine kinases in addition to the insulin receptor that regulate the action potential in cardiac myocytes. We will us pharmacologic and shRNA strategies to identify all of the tyrosine kinases in canine cardiac myocytes that signal through PI3K to regulate the APD. This comprehensive approach will facilitate the development of safer TKIs that target specific kinases involved in carcinogenesis while avoiding effects on kinases that could cause LQTS. We believe that results from these proposed studies will lead to the development of breakthrough preventive and therapeutic strategies to counter this deadly cardiac condition.