Empagliflozin inhibits intermittent hypoxia‐induced TRAF3IP2/NF‐κB/HIF‐1α/IL‐6‐dependent human aortic smooth muscle cell proliferation

Abstract

Chronic intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea and chronic obstructive pulmonary disease, contributes to cardiovascular diseases, including atherosclerosis, through persistent oxidative stress and inflammation. During atherogenesis, vascular smooth muscle cells acquire a proinflammatory and a proliferative phenotype. TRAF3IP2 (TRAF3 Interacting Protein 2) is an oxidative stress‐responsive proinflammatory adapter molecule and plays a causal role in a preclinical model of atherosclerosis. Therefore, we tested the hypothesis that IH stimulates human aortic smooth muscle cell (SMC) proliferation via TRAF3IP2, and this effect is inhibited by the SGLT2 (Sodium/Glucose Cotransporter 2) inhibitor empagliflozin. Results show that IH upregulates TRAF3IP2 expression, TRAF3IP2‐dependent superoxide, hydrogen peroxide and nitric oxide production, HIF‐1α and NF‐κB activation, IL‐6 expression, and SMC proliferation. These effects were inhibited by TRAF3IP2, NOX2, NOX4, p65 or IL6R knockdown, or pre‐exposure to potent and specific iNOS inhibitor AMT or 1400W, the JAK inhibitor Tofacitinib, the STAT3‐specific inhibitor HO‐3867, or the gp130 inhibitor SC144. Importantly, SMC express SGLT2, and pretreatment with empagliflozin abrogated IH‐induced TRAF3IP2 induction, nitroxidative stress, HIF‐1α and NF‐κB activation, IL‐6 expression, and SMC proliferation. In summary, these results suggest the therapeutic potential of empagliflozin in IH‐associated inflammatory vascular proliferative diseases.