Reduced atherosclerosis lesion size, inflammatory response in miR-150 knockout mice via macrophage effects

Abstract

Atherosclerosis is considered to be a chronic inflammatory disease that can lead to severe clinically important cardiovascular events. miR-150 is a small noncoding RNA that significantly enhances inflammatory responses by upregulating endothelial cell proliferation and migration, as well as intravascular environmental homeostasis. However, the exact role of miR-150 in atherosclerosis remains unknown. Here, we investigated the effect of miR-150 deficiency on atherosclerosis development. Using double-knockout (miR-150 and ApoE) mice, we measured atherosclerotic lesion size and stability. Meanwhile, we conducted in vivo bone marrow transplantation to identify cellular-level components of the inflammatory response. Compared with mice deficient only in ApoE, the double-knockout mice had significantly smaller atherosclerotic lesions and displayed an attenuated inflammatory response. Moreover, miR-150 ablation promoted plaque stabilization via increases in smooth muscle cell and collagen content and decreased macrophage infiltration and lipid accumulation. The in vitro experiments indicated that an inflammatory response with miR-150 deficiency in atherosclerosis results directly from upregulated expression of the cytoskeletal protein, PDZ and LIM domain 1 (PDLIM1), in macrophages. More importantly, the decreases in phosphorylated p65 expression and inflammatory cytokine secretion induced by miR-150 ablation were reversed by PDLIM1 knockdown. These findings suggest that miR-150 is a promising target for the management of atherosclerosis.

Non-coding RNAs in cardiovascular cell biology and atherosclerosis

“…In line with these observations, aortic root plaque size was reduced in Apoe-deficient mice also lacking miR-150 when compared to Apoe-deficient mice alone 171 . Additionally, plaques from miR-150 deficient mice were deemed more stable due to increased content of collagen and smooth muscle cells alongside decreased lipid and macrophage accumulation 171 . A similar athero-protective effect was detected after bone-marrow transplantation from miR-150 deficient mice into Apoe-deficient animals, implying macrophage-derived miR-150 drives atherosclerosis in this model 171 .…”

“…miR-150: Elevated circulating levels of miR-150 delineate patients with a diagnosis of unstable angina compared to patients with non-coronary chest pain (exclusion of coronary stenosis during angiogram) or healthy subjects 108 . Moreover, human coronary arteries harbouring advanced plaques demonstrated increased miR-150 expression when related to non-diseased vessels, with a similar pattern observed in high-fat fed Apoe-deficient mice 171 . In line with these observations, aortic root plaque size was reduced in Apoe-deficient mice also lacking miR-150 when compared to Apoe-deficient mice alone 171 .…”

“…Moreover, human coronary arteries harbouring advanced plaques demonstrated increased miR-150 expression when related to non-diseased vessels, with a similar pattern observed in high-fat fed Apoe-deficient mice 171 . In line with these observations, aortic root plaque size was reduced in Apoe-deficient mice also lacking miR-150 when compared to Apoe-deficient mice alone 171 . Additionally, plaques from miR-150 deficient mice were deemed more stable due to increased content of collagen and smooth muscle cells alongside decreased lipid and macrophage accumulation 171 .…”

“…Additionally, plaques from miR-150 deficient mice were deemed more stable due to increased content of collagen and smooth muscle cells alongside decreased lipid and macrophage accumulation 171 . A similar athero-protective effect was detected after bone-marrow transplantation from miR-150 deficient mice into Apoe-deficient animals, implying macrophage-derived miR-150 drives atherosclerosis in this model 171 . In vitro findings indicated miR-150 facilitates inflammation through targeting of PDLIM1 in macrophages, resulting in heightened NFκβ activation 171 .…”

ALK5 deficiency inhibits macrophage inflammation and lipid loading by targeting KLF4

“…Western blots were performed following standard protocols as previous described [16]. Briefly, the proteins were separated by SDS-PAGE and then transferred to polyvinylidene fluoride (PVDF) membranes, which were probed with the appropriate primary antibodies overnight at 4 • C. Then, the membranes were incubated with the appropriate secondary antibodies before visualization by chemiluminescence with Molecular Imager ChemiDoc TM XRS+ using Image Lab TM Software 5.1 (Bio-Rad, Bio-Legend Scientific Co. Ltd).…”