| First Author | Dingenouts CKE | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 12 | Pages | e0189805 |
| PubMed ID | 29253907 | Mgi Jnum | J:253675 |
| Mgi Id | MGI:6106496 | Doi | 10.1371/journal.pone.0189805 |
| Citation | Dingenouts CKE, et al. (2017) Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction. PLoS One 12(12):e0189805 |
| abstractText | AIMS: Hereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGFbeta 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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. |
