Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction

AIMS: 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. 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.