Linagliptin Has Wide-Ranging Anti-Inflammatory Points of Action in Human Umbilical Vein Endothelial Cells

Yuya Nakamura; Masahiro Inagaki; Mayumi Tsuji; Toshihiko Gocho; Kazuaki Handa; Hitomi Hasegawa; Akihiko Yura; Tomoko Kawakami; Isao Ohsawa; Yoshikazu Goto; Hiromichi Gotoh; Yuji Kiuchi

doi:10.4137/JCM.S39317

Linagliptin Has Wide-Ranging Anti-Inflammatory Points of Action in Human Umbilical Vein Endothelial Cells

Jpn Clin Med. 2016 Dec 5:7:27-32. doi: 10.4137/JCM.S39317. eCollection 2016.

Authors

Affiliations

¹ Department of Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan.; Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan.
² Department of Chemistry, College of Arts and Sciences, Showa University, Fujiyoshida City, Yamanashi-ken, Japan.
³ Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan.
⁴ Department of Toyosu Clinic Preventive Medicine Center, School of Medicine, Showa University, Koto-ku, Tokyo, Japan.
⁵ Department of Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan.

Abstract

Background: Because of the potential anti-inflammatory effects, linagliptin, a therapeutic dipeptidyl peptidase-4 inhibitor, is used as an effective drug for diabetic patients for whom inflammation is a prognosis-related factor. We investigated the anti-inflammatory mechanism of linagliptin using seven markers.

Methods: We pretreated human umbilical vein endothelial cells (HUVECs), with linagliptin and lipopolysaccharide (LPS). The cytosolic fractions were evaluated for protein kinase A (PKA), protein kinase B (PKB), protein kinase C (PKC), ratio of reactive oxygen species (ROS) and Cu/Zn superoxide dismutase (SOD), activator protein 1 (AP-1), and adenosine 3',5'-cyclic monophosphate (cAMP).

Results: Linagliptin increased the PKA and PKC activities and the cAMP levels in LPS-treated cells. However, it inhibited LPS-induced PKB phosphorylation, ratio of ROS and Cu/Zn SOD, and LPS-stimulated AP-1 nuclear translocation.

Conclusion: We reaffirmed the anti-inflammatory and antioxidant effects of linagliptin. These effects might be related to the three protein kinases. Our findings suggest that linagliptin has a wide range of anti-inflammatory effects.

Keywords: activator protein 1; adenosine 3′,5′-cyclic monophosphate; human umbilical vein endothelial cells; linagliptin; oxidative stress; protein kinase.