Abstract
Diabetes mellitus causes endothelial dysfunction, which further exacerbates peripheral arterial disease (PAD). Improving endothelial function via reducing endothelial oxidative stress (OS) may be a promising therapy for diabetic PAD. Activation of liver X receptor (LXR) inhibits excessive OS and provides protective effects on endothelial cells in diabetic individuals. Therefore, we investigated the effects of LXR agonist treatment on diabetic PAD with a focus on modulating endothelial OS. We used a streptozotocin‐induced diabetes mouse model combined with a hindlimb ischaemia (HLI) injury to mimic diabetic PAD, which was followed by LXR agonist treatment. In our study, the LXR agonist T0901317 protected against HLI injury in diabetic mice by attenuating endothelial OS and stimulating angiogenesis. However, a deficiency in endothelial Sirtuin1 (SIRT1) largely inhibited the therapeutic effects of T0901317. Furthermore, we found that the underlying therapeutic mechanisms of T0901317 were related to SIRT1 and non‐SIRT1 signalling, and the isoform LXRβ was involved in LXR agonist‐elicited SIRT1 regulation. In conclusion, LXR agonist treatment protected against HLI injury in diabetic mice via mitigating endothelial OS and stimulating cellular viability and angiogenesis by LXRβ, which elicited both SIRT1‐mediated and non‐SIRT1‐mediated signalling pathways. Therefore, LXR agonist treatment may be a promising therapeutic strategy for diabetic PAD.
Highlights
Peripheral arterial disease (PAD) multiplies the risk of non-traumatic amputation and afflicts over 200 million people worldwide.[1,2]Fan and Zhang contributed to this work.Diabetes mellitus (DM) increases the morbidity and severity of PAD
We explored a mouse model of hindlimb ischaemia injury (HLI) with streptozotocin (STZ)-induced DM, followed by treatment with T0901317, a non-selective liver X receptor (LXR) agonist used in our previous study,[11] to characterize the effects of LXR agonist treatment on diabetic PAD with a focus on endothelial oxidative stress (OS) and apoptosis
We found that the levels of endogenous antioxidants (SOD, CAT and GSH) in the gastrocnemius increased notably in the HLI + DM+LXR group; similar results were not observed in the HLI + DM+LXR + SIRT1endo−/− group
Summary
Peripheral arterial disease (PAD) multiplies the risk of non-traumatic amputation and afflicts over 200 million people worldwide.[1,2]. LXR agonists or genetic treatment can protect against atherosclerosis, myocardial ischaemia/reperfusion injury, myocardial hypertrophy and diabetic cardiomyopathy via repressing cellular inflammation, apoptosis and OS damage.[6,7,8,9] In addition, a previous study showed that LXR agonist treatment inhibits high glucose (HG)-induced endothelial OS and senescence, with an additional atheroprotective effect in diabetes.[10] we hypothesized that LXR agonist treatment might inhibit endothelial OS and apoptosis, further promoting angiogenesis and protecting against diabetic PAD. We used endothelial-specific SIRT1 knockout mice treated with T0901317 to investigate the interaction between SIRT1 and LXR and evaluate the potential effects of LXR agonist treatment on diabetic PAD
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