Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Cardiovasc Ther. 2013 Oct;31(5):259-67. doi: 10.1111/1755-5922.12005.
Following myocardial infarction (MI), individuals with diabetes have a two-fold increase in the risk of heart failure, due in part to excessive loss of cardiac microvasculature. Endothelial integrity and restitution are mediated in part by stromal cell-derived factor-1α (SDF-1α), a chemokine that is elaborated by ischemic tissue but rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Accordingly, we hypothesized that inhibiting this enzyme may confer benefit following myocardial infarction in the diabetic setting beyond its effect on glycemia.
Fischer F344 rats with streptozotocin (STZ)-diabetes were randomized to receive vehicle or the DPP-4 inhibitor, sitagliptin (300 mg/kg/day). Two weeks later, animals underwent experimental MI, induced by ligation of the left anterior descending coronary artery. Cardiac function was assessed by conductance catheterization and echocardiography along with cardiac structure 4 weeks post-MI. Following MI, untreated diabetic rats developed both systolic and diastolic cardiac dysfunction, in association with endothelial cell loss, fibrosis, and myocyte hypertrophy. Without affecting plasma glucose, sitagliptin treatment led to an improvement in passive left ventricular compliance, increased endothelial cell density, reduced myocyte hypertrophy, and a reduction in the abundance of collagen 1 (all P < 0.05). Systolic function was unchanged.
This study shows that DPP-4 inhibition attenuates several, but not all, aspects of cardiac dysfunction and adverse remodeling in the post-MI setting.
心肌梗死（MI）后，糖尿病个体心力衰竭的风险增加了两倍，部分原因是心脏微血管过度丧失。基质细胞衍生因子-1α（SDF-1α）介导内皮完整性和修复，SDF-1α 是一种趋化因子，由缺血组织产生，但很快被二肽基肽酶-4（DPP-4）降解。因此，我们假设抑制这种酶可能会在糖尿病患者发生心肌梗死后带来益处，其作用不仅限于对血糖的影响。
链脲佐菌素（STZ）诱导的糖尿病 Fischer F344 大鼠随机分为接受载体或 DPP-4 抑制剂西他列汀（300mg/kg/天）。两周后，通过结扎左前降支冠状动脉诱导动物发生实验性 MI。MI 后 4 周通过心导管术和超声心动图评估心功能，并评估心脏结构。未经治疗的糖尿病大鼠在 MI 后出现收缩期和舒张期心脏功能障碍，伴有内皮细胞丢失、纤维化和心肌细胞肥大。西他列汀治疗不影响血浆葡萄糖水平，但可改善被动左心室顺应性、增加内皮细胞密度、减少心肌细胞肥大，并减少胶原 1 的含量（均 P<0.05）。收缩功能没有变化。
本研究表明，DPP-4 抑制可减轻 MI 后心脏功能障碍和不良重构的几个方面，但不是所有方面。
