Dipeptidyl peptidase IV (DPP-4) is well known for its role in glucose homeostasis, and DPP-4 inhibitor (DPP-4i) exhibits multiple actions in cardiovascular diseases. However, the effect of DPP-4i on pulmonary hypertension (PH) remains unclear. Therefore, this study aims to investigate the effect of DPP-4i on pulmonary arterial remodeling in rats with PH and the potential underlying mechanisms. Our results show that DPP-4 was expressed in epithelial cells, endothelial cells, smooth muscle cells, and inflammatory cells in lung. DPP-4i (Sitagliptin) attenuated right ventricular systolic pressure (RVSP), right ventricle remodeling, hypertrophy of pulmonary arterial medial layer, inflammatory cell infiltration, and endothelial-mesenchymal transition (EndMT) in monocrotaline (MCT)-induced PH rats. Similarly, DPP-4i also alleviated bleomycin- and chronic hypoxia-induced PH in rats. In cultured human pulmonary arterial smooth muscle cells (PASMCs), DPP-4i inhibited platelet derived growth factor (PDGF)-BB-induced proliferation and migration, which was abolished by phosphatase and tensin homolog deleted on chromosome ten (PTEN) knockout. These results demonstrate that DPP-4 inhibition alleviates pulmonary arterial remodeling in experimental PH by inhibiting proliferation and migration of PASMCs.

Acute lung injury (ALI) is a devastating critical disease characterized by diffuse inflammation and endothelial dysfunction. Increasing evidence, including from our laboratory, has revealed that the opening of ATP-sensitive potassium (KATP) channels has promising anti-inflammation and endothelial protection activities in various disorders. However, the impacts of KATP channels on ALI remain obscure. In this study, we used nicorandil (Nico), a classic KATP channel opener, to investigate whether opening of KATP channels could alleviate ALI with an emphasis on human pulmonary artery endothelial cell (HPAEC) modulation. The results showed that Nico inhibited lipopolysaccharide- (LPS-) induced inflammatory response, protein accumulation, myeloperoxidase activity, and endothelial injury. In vitro, Nico reduced LPS-induced HPAEC apoptosis and the expression of cleaved-caspase-3, caspase-9, and CCAAT/enhancer-binding protein homologous protein (CHOP). Additionally, Nico inhibited inflammation by suppressing monocyte-endothelial adhesion and decreasing the expression of proinflammatory proteins. Moreover, Nico restored the expression and the distribution of adherens junction vascular endothelial- (VE-) cadherin. Further, Nico abolished the increase in intracellular reactive oxygen species (ROS) and the activation of NF-κB and mitogen-activated protein kinase (MAPK) in HPAECs. Glibenclamide (Gli), a nonselective KATP channel blocker, abrogated the effects of Nico, implying that opening of KATP channels contributes to the relief of ALI. Together, our findings indicated that Nico alleviated LPS-induced ALI by protecting ECs function via preventing apoptosis, suppressing endothelial inflammation and reducing oxidative stress, which may be attributed to the inhibition of NF-κB and MAPK signaling pathways.

Accumulating data, including those from our laboratory, have shown that the opening of ATP‐sensitive potassium channels (KATP) plays a protective role in pulmonary vascular diseases (PVD). As maintainers of the endothelial framework, endothelial colony‐forming cells (ECFCs) are considered excellent candidates for vascular regeneration in cases of PVD. Although KATP openers (KCOs) have been demonstrated to have beneficial effects on endothelial cells, the impact of KATP on ECFC function remains unclear. Herein, this study investigated whether there is a distribution of KATP in ECFCs and what role KATP play in ECFC modulation. By human ECFCs isolated from adult peripheral blood, KATP were confirmed for the first time to express in ECFCs, comprised subunits of Kir (Kir6.1, Kir6.2) and SUR2b. KCOs such as the classical agent nicorandil (Nico) and the novel agent iptakalim (Ipt) notably improved the function of ECFCs, promoting cell proliferation, migration and angiogenesis, which were abolished by a non‐selective KATP blocker glibenclamide (Gli). To determine the underlying mechanisms, we investigated the impacts of KCOs on CaMKII, Akt and endothelial nitric oxide synthase pathways. Enhanced levels were detected by western blotting, which were abrogated by Gli. This suggested an involvement of Ca2+ signalling in the regulation of ECFCs by KATP. Our findings demonstrated for the first time that there is a distribution of KATP in ECFCs and KATP play a vital role in ECFC function. The present work highlighted a novel profile of KATP as a potential target for ECFC modulation, which may hold the key to the treatment of PVD.