Dingenouts Calinda K E, Bakker Wineke, Lodder Kirsten, Wiesmeijer Karien C, Moerkamp Asja T, Maring Janita A, Arthur Helen M, Smits Anke M, Goumans Marie-José
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom.
PLoS One. 2017 Dec 18;12(12):e0189805. doi: 10.1371/journal.pone.0189805. eCollection 2017.
Hereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGFβ co-receptor endoglin. Dysfunctional homing of HHT1 mononuclear cells (MNCs) towards the infarcted myocardium hampers cardiac recovery. HHT1-MNCs have elevated expression of dipeptidyl peptidase-4 (DPP4/CD26), which inhibits recruitment of CXCR4-expressing MNCs by inactivation of stromal cell-derived factor 1 (SDF1). We hypothesize that inhibiting DPP4 will restore homing of HHT1-MNCs to the infarcted heart and improve cardiac recovery.
After inducing myocardial infarction (MI), wild type (WT) and endoglin heterozygous (Eng+/-) mice were treated for 5 days with the DPP4 inhibitor Diprotin A (DipA). DipA increased the number of CXCR4+ MNCs residing in the infarcted Eng+/- hearts (Eng+/- 73.17±12.67 vs. Eng+/- treated 157.00±11.61, P = 0.0003) and significantly reduced infarct size (Eng+/- 46.60±9.33% vs. Eng+/- treated 27.02±3.04%, P = 0.03). Echocardiography demonstrated that DipA treatment slightly deteriorated heart function in Eng+/- mice. An increased number of capillaries (Eng+/- 61.63±1.43 vs. Eng+/- treated 74.30±1.74, P = 0.001) were detected in the infarct border zone whereas the number of arteries was reduced (Eng+/- 11.88±0.63 vs. Eng+/- treated 6.38±0.97, P = 0.003). Interestingly, while less M2 regenerative macrophages were present in Eng+/- hearts prior to DipA treatment, (WT 29.88±1.52% vs. Eng+/- 12.34±1.64%, P<0.0001), DPP4 inhibition restored the number of M2 macrophages to wild type levels.
In this study, we demonstrate that systemic DPP4 inhibition restores the impaired MNC homing in Eng+/- animals post-MI, and enhances cardiac repair, which might be explained by restoring the balance between the inflammatory and regenerative macrophages present in the heart.
1型遗传性出血性毛细血管扩张症（HHT1）是一种由转化生长因子β（TGFβ）共受体内皮糖蛋白单倍体不足引起的遗传性血管疾病。HHT1单核细胞（MNCs）向梗死心肌的归巢功能障碍阻碍了心脏恢复。HHT1-MNCs中二肽基肽酶-4（DPP4/CD26）表达升高，其通过使基质细胞衍生因子1（SDF1）失活来抑制表达CXCR4的MNCs的募集。我们假设抑制DPP4将恢复HHT1-MNCs向梗死心脏的归巢并改善心脏恢复。
诱导心肌梗死（MI）后，野生型（WT）和内皮糖蛋白杂合子（Eng+/-）小鼠用DPP4抑制剂二肽基肽酶抑制剂A（DipA）治疗5天。DipA增加了梗死Eng+/-心脏中CXCR4+MNCs的数量（Eng+/-组73.17±12.67 vs. DipA治疗的Eng+/-组157.00±11.61，P = 0.0003），并显著减小了梗死面积（Eng+/-组46.60±9.33% vs. DipA治疗的Eng+/-组27.02±3.04%，P = 0.03）。超声心动图显示，DipA治疗使Eng+/-小鼠的心功能略有恶化。在梗死边缘区检测到毛细血管数量增加（Eng+/-组61.63±1.43 vs. DipA治疗的Eng+/-组74.30±1.74，P = 0.001），而动脉数量减少（Eng+/-组11.88±0.63 vs. DipA治疗的Eng+/-组6.38±0.97，P = 0.003）。有趣的是，虽然在DipA治疗前Eng+/-心脏中M2再生巨噬细胞较少（WT组29.88±1.52% vs. Eng+/-组12.34±1.64%，P<0.0001），但DPP4抑制使M2巨噬细胞数量恢复到野生型水平。
在本研究中，我们证明全身DPP4抑制可恢复MI后Eng+/-动物受损的MNC归巢，并增强心脏修复，这可能是通过恢复心脏中炎症性巨噬细胞和再生性巨噬细胞之间的平衡来解释的。
