Fellow or Postdoc
Shruti Rawal, Vinay Randhawa, Syed Husain Mustafa Rizvi, Madhur Sachan, AKM Khyrul Wara, Daniel Pérez-Cremades, Robert M Weisbrod, Naomi M Hamburg, and Mark W. Feinberg.
Mark W. Feinberg
Dysregulated macrophage metabolism and function contributes to diabetes-accelerated atherosclerosis. Identifying critical factors to restore immunometabolic alterations remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages and regulate inflammation, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear. miRNA-profiling of aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing diet for 12 weeks revealed low expression of miR-369-3p. miR-369-3p was also reduced in peripheral blood mononuclear cells from diabetic patients with coronary artery disease. Cell-type expression profiling showed miR-369-3p enrichment in primary mouse macrophages, which was downregulated upon oxLDL-stimulation. Metabolic profiling in mouse macrophages revealed oxLDL-mediated increase in pro-inflammatory metabolite succinate and its receptor(GPR91), which were mitigated by miR-369-3p overexpression. In a mice model of diabetes-accelerated atherosclerosis, therapeutic administration of miR-369-3p, attenuated plaque progression, evident by reduced plaque size. RNA-seq in plaque macrophages identified pro-resolving pathways enriched in miR-369-3p treated mice, and a corresponding increase in macrophage functionality (efferocytosis). Mechanistically, we discovered succinate receptor GPR91 as a novel target of miR-369-3p. Overexpression of miR-369-3p, both in vitro and in vivo, downregulated succinate-GPR91-NLRP3 axis, thereby reducing inflammasome activation. Our findings establish a novel therapeutic role of miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage metabolism.
Globally, about 6.7 million people die every year due to diabetes. In the US, about 37.3 million people are diabetic with 1 in 5 being undiagnosed. Diabetic patients are atleast twice as likely to get heart disease, and at a younger age. Diabetes can lead to a condition called atherosclerosis, which is the buildup of fatty deposits (plaque) inside our arteries. This plaque is like gunk that narrows the arteries, making it hard for blood to flow smoothly. It’s a big problem because it can lead to heart attacks and strokes. To halt this, our immune cells clear the fatty plaques and unclog the blood vessels. However, diabetes causes dysfunctional immune cells, leading to build-up of fatty plaques, progressing to advanced atherosclerosis. We have discovered a tiny molecule called microRNA-369-3p which may act like a traffic cop, helping to control the inflammation that happens when you have diabetes. We investigated the role of microRNA-369-3p using laboratory mouse models that mimic diabetes and atherosclerosis conditions like humans. We also confirmed our findings in human samples from patients with diabetes and atherosclerosis. This exciting discovery brings hope for new treatments to keep our hearts healthy, even when diabetes is in the picture.