DPP-4 inhibition: А novel therapeutic approach to the treatment of pulmonary hypertension?

Abstract

Pulmonary hypertension (PH) is a progressive disorder characterized by alterations of the vascular structure and function in the lungs. Despite the success in its stabilisation by targeting pulmonary vascular tone and endothelial dysfunction, the prognosis remains poor and new therapeutic approaches via neglected macromolecular targets are needed. In the pathophysiology of PH the early stages of vascular remodelling are considered to be reversible, while endothelial to mesenchymal transition and proliferation/migration of fibroblasts play a critical role in staging the irreversible phase. Dipeptidyl peptidase-4 (DPP-4)/CD26 is present and active in the lungs and is expressed constitutively on lung fibroblasts, on which it exerts proliferative effects. Further, it is a marker of migrating fibroblasts and of their functional activation, including collagen synthesis and inflammatory cytokine secretion. Inhibiting DPP-4 improves the reversible phases of vascular dysfunction in PH, but is also highly likely to attenuate endothelial to mesenchymal transition and decrease the proliferation and migration of fibroblasts, preventing fibrosis and, consequently, should prolong or even inhibit entrance to the potentially irreversible phase of PH. Proposed mechanisms that support the multifaceted aspects of DPP-4 inhibition in terms of improving PH, involve pathways and mediators in pulmonary vascular and connective tissue remodelling. The latter are affected by the inhibition of this protease resulting in the synergistic beneficial antioxidative, anti-inflammatory and antifibrotic effects. We offer here an evidence-supported hypothesis that DPP-4 inhibitors are likely to be effective in the irreversible phase of remodelling in PH. Accordingly, we propose PH as a possible novel therapeutic indication for existing and new DPP-4 inhibitors.

Keywords: Dipeptidyl peptidase-4 inhibition; Fibroblast proliferation and migration; Pulmonary hypertension; Pulmonary vascular remodelling; microRNA.