miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling

Shruti Rawal; Vinay Randhawa; Syed Husain Mustafa Rizvi; Madhur Sachan; Akm Khyrul Wara; Daniel Pérez-Cremades; Robert M Weisbrod; Naomi M Hamburg; Mark W Feinberg

doi:10.1093/cvr/cvae102

miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling

Cardiovasc Res. 2024 May 4:cvae102. doi: 10.1093/cvr/cvae102. Online ahead of print.

Authors

Shruti Rawal¹, Vinay Randhawa¹, Syed Husain Mustafa Rizvi², Madhur Sachan¹, Akm Khyrul Wara¹, Daniel Pérez-Cremades^{1

3}, Robert M Weisbrod², Naomi M Hamburg², Mark W Feinberg¹

Affiliations

¹ Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA; Cardiology, Whitaker Cardiovascular Institute, And Boston University School of Medicine, Boston, MA, USA.
³ Department of Physiology, University of Valencia, and INCLIVA Biomedical Research Institute, Valencia 46010, Spain.

PMID: 38703377
DOI: 10.1093/cvr/cvae102

Abstract

Aims: Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear.

Methods and results: MiRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells (PBMCs) from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxLDL-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation (lL-1β, TNF-a, IL-6). Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signaling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes.

Conclusion: These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

Keywords: GPR91; atherosclerosis; diabetes; macrophage; microRNA; succinate.

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