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）是一种可能致命的心脏疾病，可由药物引起，也与糖尿病有关。QT间期延长在糖尿病人群中的患病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风险因素。最近癌症治疗的一个主要进展是开发了抑制酪氨酸激酶、磷酸肌醇3-激酶（PI 3 K）和在致癌作用中起关键作用的其他信号分子的靶向疗法。酪氨酸激酶抑制剂（TKI）显著改善了慢性髓性白血病等癌症患者的生存率，目前在临床试验中的几种PI 3 K抑制剂也显示出有希望的抗癌活性。然而，这些药物可能会导致LQTS。我们研究了这些药物诱导的LQTS的起源，并惊讶地发现心脏动作电位时程（APD）的延长并不完全是由于复极钾电流IKr的减少。相反，正如我们最近在Science Translational Medicine上报道的那样，多个电流（IKr，IKs，ICaL和峰值INa）减少，而持久（持续）钠电流（INaP）增加。TKI通过抑制PI 3 K信号传导引起这些效应。已充分确定糖尿病与胰岛素响应性组织（包括心脏）中PI 3 K信号传导减少相关。因此，我们的主要假设是，糖尿病患者心脏PI 3 K信号转导降低加重了药物诱导的LQTS的风险。我们将使用两种糖尿病小鼠模型的心肌细胞和心脏以及胰岛素/PI 3 K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PI 3 K信号传导改善药物诱导的LQTS。我们提出的研究将确定胰岛素/葡萄糖/钾输注是否逆转犬体内药物诱导的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策略来鉴定犬心肌细胞中通过PI 3 K信号调节APD的所有酪氨酸激酶。这种综合方法将有助于开发更安全的TKI，靶向参与致癌作用的特定激酶，同时避免对可能导致LQTS的激酶产生影响。我们相信，这些研究的结果将导致突破性的预防和治疗策略的发展，以应对这种致命的心脏病。

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.