MicroRNA-590 Inhibits Lipoprotein Lipase Expression and Prevents Atherosclerosis in apoE Knockout Mice

Abstract

Recent studies have suggested that miR-590 may play critical roles in cardiovascular disease. This study was designed to determine the effects of miR-590 on lipoprotein lipase (LPL) expression and development of atherosclerosis in apolipoprotein E knockout (apoE−/−) mice and explore the potential mechanisms. En face analysis of the whole aorta revealed that miR-590 significantly decreased aortic atherosclerotic plaque size and lipid content in apoE−/− mice. Double immunofluorescence staining in cross-sections of the proximal aorta showed that miR-590 agomir reduced CD68 and LPL expression in macrophages in atherosclerotic lesions. MiR-590 agomir down-regulated LPL mRNA and protein expression as analyzed by RT-qPCR and western blotting analyses, respectively. Consistently, miR-590 decreased the expression of CD36 and scavenger receptor A1 (SRA1) mRNA and protein. High-performance liquid chromatography (HPLC)analysis confirmed that treatment with miR-590 agomir reduced lipid levels either in plasma orinabdominal cavity macrophages of apoE−/− mice. ELISA analysis showed that miR-590 agomir decreased plasma levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin-1β (IL-1β)and interleukin-6 (IL-6). In contrast, treatment with miR-590 antagomir prevented or reversed these effects. Taken together, these results reveal a novel mechanism of miR-590 effects, and may provide new insights into the development of strategies for attenuating lipid accumulation and pro-inflammatory cytokine secretion.

MiR‐590 Promotes Transdifferentiation of Porcine and Human Fibroblasts Toward a Cardiomyocyte‐Like Fate by Directly Repressing Specificity Protein 1

“…The miR‐590 family, more specifically, which is comprised of 2 miRNAs—miR‐590‐5p and miR‐590‐3p—is thought to play a key role in cardiovascular disease through its protection of blood vessels, regulation of lipid metabolism, and prevention of myocarditis and atherosclerosis through its target genes . miR‐590 is expressed in human induced pluripotent stem‐cell‐derived cardiomyocytes and in the human heart .…”

“…26 The miR-590 family, more specifically, which is comprised of 2 miRNAs-miR-590-5p and miR-590-3p-is thought to play a key role in cardiovascular disease through its protection of blood vessels, regulation of lipid metabolism, and prevention of myocarditis and atherosclerosis through its target genes. [27][28][29] miR-590 is expressed in human induced pluripotent stem-cell-derived cardiomyocytes and in the human heart. 30,31 miR-590 regulates signaling pathways (TGF-b, protein kinase B) involved in cardiac fibrosis/remodeling, embryonic stem cell proliferation/cardiac differentiation, and metabolism by suppressing TGF-b receptor II.…”

Role of microRNAs in the Development of Cardiovascular Disease in Systemic Autoimmune Disorders

“…There is growing evidence that miRNAs control these pathologic processes including endothelial dysfunction (miR let-7g, mir-17-3p, miR-31, miR-146a, miR-155, miR-181 family, miR-221/-222,) [170][171][172][173][174][175], oxidative stress (miR-let-7a/b, miR-19b, miR-20a, miR-98, miR-126, miR-142-3p, miR-199a-3p and -5p, miR-200c, miR-221, miR-222, miR-328) [176][177][178][179][180][181][182][183][184][185][186][187][188][189], monocyte recruitment, differentiation and activation (miR-21, miR-23a-5p, miR-27a/b, miR-33, miR-34, miR-146a, miR-155, miR-212, miR-451, miR-590, miR-758-5p, [190][191][192][193][194][195][196][197][198][199][200][201] and inflammation/secretion of inflammatory cytokines (miR let-7g, miR-17-3p, miR-31, miR-146a, miR-155, miR-181a-3p/-5p, miR-181b, miR-221 and miR-222) [171,202,203]. Interestingly, a number of them are simultaneously involved in all those processes, suggesting common and/or cooperative activities, and underlying their relevance in the physiopathology of CVD.…”

MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

“…miR-34 increases the binding capacity of oxLDL to macrophages by facilitating bridging between lipoprotein lipase (LPL) and LOX-1 [79]. Conversely, miR-27 and miR-590 inhibit LPL expression to prevent macrophage lipid accumulation and cytokine release [77,80,81].…”