Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages

Tharini Sivasubramaniyam,Alexandra Zyla,Rickvinder Besla,Jiaqi Yang,Min Jeong Kim ,Daniella Febbraro,David W Dodington,Raymond H Kim ,Henry S Cheng,Sally Yu Shi,Jacques Genest,Clinton S Robbins,Isabelle L Ruel ,Xavier S Revelo,Daniel A Winer,Angela Li,Yoo Jin Park ,Tak W Mak,Helen Le,Stephanie A Schroer,Idit Dotan,Minna Woo

doi:10.1038/s41598-021-84063-6

Abstract

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1−/−Apoe−/−). After 21 weeks of atherogenic diet, Dj1−/− Apoe−/−mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

Highlights

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion
Atherosclerosis-prone apolipoprotein E-null (Apoe−/−) mice placed on a high cholesterol high fat diet (HCD; 0.2% cholesterol; 60% kcal of fat) for 16 weeks showed a significant increase in serum Dj-1 levels compared to Apoe−/− mice on normal chow diet (NCD) (0.02% cholesterol; 17% kcal of fat) (Fig. 1a)
We investigated the role of Dj1 in the pathogenesis of atherosclerosis

Summary

Introduction

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. Cardiovascular diseases (CVD) stemming largely from atherosclerosis remain the leading cause of morbidity and mortality globally despite recent therapeutic advances. Atherosclerosis is a chronic inflammatory disease characterized by the narrowing of blood vessels by the growth of lipid-rich plaques. Overabundance of plasma lipids from genetic predisposition and cholesterol-rich diets elevates the circulatory levels of oxidized lowdensity lipoproteins (oxLDL) and promotes their deposition in vessel walls eliciting an inflammatory response. Potential paradoxical beneficial role of ROS in cardiovascular pathophysiology has stimulated investigation of antioxidant proteins as potential therapeutic interventions in atherosclerosis

Methods

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Conclusion