Jingshu Chen, PhD
Jingshu Chen, Anurag Jamaijar, Grasiele Sausen, Henry S. Cheng, Aspasia Tzani, Carmel Assa, Samuel Eley, Jorge Plutzky,Mark W. Feinberg
Research Category: Cardiovascular, Diabetes, and Metabolic Disorders, Cardiovascular/Diabetes/Metabolic Disorders
Diabetes-associated atherosclerosis is characterized by accelerated immune cell infiltration and plaque formation in the vessel wall. Macrophages are instrumental for lesion formation, however the mechanisms underlying their impaired function remain poorly understood. Herein, we identify a novel macrophage-enriched lncRNA MERRICAL (Macrophage Enriched lncRNA Regulates Inflammation, Chemotaxis, and AtheroscLerosis) in diabetes-associated atherosclerosis. LncRNA MERRICAL is nuclear localized and increased by 249% in lesions during progression in Ldlr-/- mice under a high fat, high sucrose (HFSC) diet. Transcriptomic analysis of MERRICAL-deficient macrophages showed decreased chemokine and inflammatory gene expression with less activated chemotaxis and inflammatory-associated gene ontology pathways. Gain- and loss-of-function studies demonstrated the role of MERRICAL in cis-regulation of its neighboring genes Ccl3 and Ccl4, an effect that is mediated in part via interaction with H3K4me3. Remarkably, systemic knockdown of MERRICAL in HFSC-fed mice reduced lesion formation by 73% in the aortic sinus and 86% in the descending aorta, independent of effects on the lipid profile, but rather by inhibiting the pro-inflammatory and Ccl3- and Ccl4-associated chemotactic response and decreasing the recruitment of leukocytes into the aortic wall. These findings establish a cis-regulatory mechanism by which a macrophage-specific lncRNA potently inhibits pro-inflammatory and chemotactic responses to alleviate lesion progression in diabetes.
Atherosclerosis is the buildup of fats, cholesterol and other substances in and on the artery walls. This buildup is called plaque. The plaque can cause your arteries to narrow, blocking blood flow. The plaque can also burst, leading to a blood clot. Atherosclerosis involves many factors in different types of cells. Macrophages play a central role in the development of plaques. Many genes are found to regulate the function of macrophages during the development of atherosclerosis, but the underlying mechanism is not clear. Long noncoding RNAs are new transcripts in the genome that do not make a protein but control important processes involved in many diseases. In this study, we discovered a new macrophage specific long noncoding RNA, MERRICAL, regulating inflammation and recruitment of macrophages in the artery walls. Our gain- and loss-of-function studies showed MERRICAL regulated its neighboring genes Ccl3 and Ccl4 expression. Remarkably, inhibiting expression of MERRICAL in the mice under a diabetic diet showed 73% reduced plaque formation in the aortic sinus and 86% in the descending aorta. Our study showed a better understanding of the functions of macrophages in the buildup of plaque in the blood vessel wall in diabetic atherosclerosis. These new findings may provide new targets for therapies.