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miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signalling
Shruti Rawal1, Vinay Randhawa1, Syed Husain Mustafa Rizvi2,3
1Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
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 orchestrate multiple signalling 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 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 oxidized low density lipoprotein (oxLDL)-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation [Interleukin (lL)-1β, TNF-α, and IL-6]. Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signalling 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.
Insights
MicroRNA-369-3p (miR-369-3p) can halt diabetes-accelerated atherosclerosis by targeting the succinate receptor GPR91. Restoring miR-369-3p levels in macrophages reduces inflammation and plaque size.
Area of Science:
- Cardiovascular Research
- Immunometabolism
- Molecular Biology
Background:
- Diabetes mellitus accelerates atherosclerosis by dysregulating macrophage immunometabolism.
- MicroRNAs (miRNAs) play a role in cellular signaling, but their therapeutic potential in diabetes-associated atherosclerosis is largely unexplored.
- Identifying novel targets to restore metabolic balance and resolve inflammation in diabetic atherosclerosis is crucial.
Purpose of the Study:
- To investigate the role of miR-369-3p in diabetes-accelerated atherosclerosis.
- To determine if miR-369-3p can modulate macrophage metabolism and inflammation.
- To explore the therapeutic potential of miR-369-3p in a mouse model of atherosclerosis.
Main Methods:
- miRNA profiling in mouse aortic lesions and human peripheral blood mononuclear cells.
- In vitro studies using oxidized low-density lipoprotein (oxLDL) treated bone marrow-derived macrophages (BMDMs).
- Metabolic profiling, RNA sequencing, and therapeutic administration of miR-369-3p mimics in Ldlr-/- mice.
- Assessment of plaque size, inflammatory markers, and macrophage efferocytosis.
Main Results:
- Reduced miR-369-3p expression was observed in atherosclerotic lesions of diabetic mice and patients with coronary artery disease.
- miR-369-3p overexpression in macrophages blocked oxLDL-induced succinate increase, reduced mitochondrial respiration, and suppressed inflammation.
- miR-369-3p directly targeted GPR91, alleviating oxLDL-induced inflammasome activation.
- Therapeutic miR-369-3p administration reduced plaque size, inflammatory cell infiltration, and enhanced efferocytosis in mice.
- A GPR91 antagonist reduced oxLDL-induced inflammation in human diabetic monocytes.
Conclusions:
- miR-369-3p acts as a critical regulator of macrophage immunometabolism in diabetes-associated atherosclerosis.
- Targeting GPR91 with miR-369-3p offers a potential therapeutic strategy for halting atherosclerosis progression in diabetic patients.
- Restoring miR-369-3p levels can promote resolution of inflammation and improve atherosclerotic plaque characteristics.
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