Inhibiting Dpp4 In A Mouse Model Of Hht1 Results In A Shift Towards Regenerative Macrophages And Reduces Fibrosis After Myocardial Infarction

AimsHereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGF beta 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 resultsAfter 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.ConclusionsIn 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.