Heart Institute.
Circ Heart Fail. 2013 Sep 1;6(5):1029-38. doi: 10.1161/CIRCHEARTFAILURE.112.000057. Epub 2013 Jul 26.
The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated.
Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of ≈130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (≈50%) and heart tissue (≈3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion.
Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.
本研究旨在验证二肽基肽酶 IV（DPPIV）活性与心力衰竭（HF）不良预后相关的假设，DPPIV 是一种使具有心脏保护作用的肽失活的酶。还研究了 DPPIV 抑制在预防心脏功能障碍方面的治疗潜力。
在 190 例 HF 患者和 42 例对照者的血液样本中测量 DPPIV 活性，结果显示 HF 患者的循环 DPPIV 活性增加了约 130%，与健康受试者相比。此外，HF 患者的血清 DPPIV 活性与左心室（LV）射血分数呈负相关。同样，与假手术大鼠相比，射频 LV 消融诱导 HF 大鼠的血浆（≈50%）和心脏组织（≈3.5 倍）中的 DPPIV 活性更高。此外，血浆 DPPIV 活性与 LV 舒张末期压和肺充血呈正相关。手术 2 天后，一组射频 LV 消融诱导 HF 大鼠接受 DPPIV 抑制剂西他列汀（40 mg/kg BID）治疗 6 周，而其余大鼠给予水。血流动力学测量结果表明，接受西他列汀治疗的射频 LV 消融大鼠显著减轻了 HF 相关的心脏功能障碍，包括 LV 舒张末期压、收缩性能和心室僵硬度。西他列汀治疗还减轻了心脏重构和心肌细胞凋亡，并最大限度地减少了肺充血。
总的来说，本文的结果将循环 DPPIV 活性与人类和实验性 HF 较差的心血管预后联系起来。此外，结果表明，长期 DPPIV 抑制可减轻大鼠 HF 的发生和进展。
