Koyani Chintan N, Kolesnik Ewald, Wölkart Gerald, Shrestha Niroj, Scheruebel Susanne, Trummer Christopher, Zorn-Pauly Klaus, Hammer Astrid, Lang Petra, Reicher Helga, Maechler Heinrich, Groschner Klaus, Mayer Bernd, Rainer Peter P, Sourij Harald, Sattler Wolfgang, Malle Ernst, Pelzmann Brigitte, von Lewinski Dirk
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria.
Biochem Pharmacol. 2017 Dec 1;145:64-80. doi: 10.1016/j.bcp.2017.08.021. Epub 2017 Aug 30.
Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca-ATPase 2a axis and Na-Ca exchanger function in Ca extrusion. This resulted in reduced sarcoplasmic reticulum Ca content, diastolic Ca overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.
在2型糖尿病患者中，使用沙格列汀治疗与心力衰竭住院率增加有关，尽管其潜在机制仍不清楚。为了解决这个问题，我们评估了沙格列汀对人心房小梁、豚鼠心脏和心肌细胞的影响。我们发现，心肌细胞中不存在沙格列汀的主要靶点二肽基肽酶-4，但沙格列汀可内化进入心肌细胞，并通过抑制钙/钙调蛋白依赖性蛋白激酶II-受磷蛋白-肌浆网钙-ATP酶2a轴以及钠-钙交换体在钙外排中的功能，损害心脏收缩力。这导致肌浆网钙含量减少、舒张期钙超载、收缩功能障碍和收缩力受损。此外，沙格列汀降低了蛋白激酶C介导的延迟整流钾电流，延长了动作电位时程，从而延长了QTc间期。重要的是，沙格列汀加重了由缺血/再灌注损伤引起的原有心脏功能障碍。总之，我们的新结果为沙格列汀对心脏功能的脱靶有害作用提供了机制，并支持了SAVOR-TIMI 53试验中沙格列汀与心力衰竭风险相关的结果。
