The miR-378c-Samd1 circuit promotes phenotypic modulation of vascular smooth muscle cells and foam cells formation in atherosclerosis lesions

Abstract

MicroRNAs have emerged as key regulators in vascular diseases and are involved in the formation of atherosclerotic lesions. However, the atherosclerotic-specific MicroRNAs and their functional roles in atherosclerosis are unclear. Here, we report that miR-378c protects against atherosclerosis by directly targeting Sterile Alpha Motif Domain Containing 1 (Samd1), a predicted transcriptional repressor. miR-378c was strikingly reduced in atherosclerotic plaques and blood of acute coronary syndrome (ACS) patients relative to healthy controls. Suppression of miR-378c promoted vascular smooth muscle cells (VSMCs) phenotypic transition during atherosclerosis. We also reported for the first time that Samd1 prolonged immobilization of LDL on the VSMCs, thus facilitated LDL oxidation and subsequently foam cell formation. Further, we found that Samd1 contains predicted DNA binding domain and directly binds to DNA regions as a transcriptional repressor. Together, we uncovered a novel mechanism whereby miR-378c-Samd1 circuit participates in two key elements of atherosclerosis, VSMCs phenotypic transition and LDL oxidation. Our results provided a better understanding of atherosclerosis pathophysiology and potential therapeutic management by targeting miR-378c-Samd1 circuit.

SAMD1 Distribution Patterns in Mouse Atherosclerosis Models Suggest Roles in LDL Retention, Antigen Presentation, and Cell Phenotype Modulation

“…It is also consistent with a recent finding that both up-and down-regulation of multiple pathways was seen in SAMD1 KO ES cells, including up-regulation of muscle cell migration [5]. In contrast, another study found that upregulation rather than downregulation of SAMD1 caused phenotype changes in VSMCs [3]. In apoE-/-mice after 16 weeks on HFD, medial SMC markers are reduced and some medial SMCs are expressing CD68 [52], suggesting additional phenotype changes that correlate with reduced SAMD1 staining.…”

“…Only 2 days after injury, there is a 60% reduction in the number of medial SMCs [28]; medial SMCs rapidly dedifferentiate, migrate to the intima, and proliferate such that at two weeks, about 80% of cells in the developing neointima are SMC, many of these have differentiated to macrophage-like foam cells [29], [30]. We thus hypothesize that SAMD1 expressed by intimal SMCs is the LDL binding molecule [2], [3], that gradually comes into effect in spontaneous lesions as intimal SMCs migrate and proliferate, starting between weeks 8 and 12 [31].…”

“…In mouse models, LDL antigenicity may be induced by luminal interaction with ECs, during EC LDL transport, and/or during subendothelial retention [34]. A recent study reports that LDL binding to SAMD1 on SMC surfaces induced LDL oxidation [3], so the SAMD1/apoB complex may be antigenic soon after formation. Stimulated ECs recruit and retain platelets, and release extracellular vesicles [39].…”

“…SAMD1, once in the ECM and at the cell surface, is accessible to bind perfusing LDL. VSMC phenotype modulation can not only be induced by SAMD1 up-and down-regulation, but increasing and suppressing SAMD1 expression on the outside surface of the VSMC cell membrane increases and decreases retained LDL, oxLDL, and foam cell formation [3].…”

“…A recent paper strongly supports SAMD1's participation in atherosclerosis. SAMD1-miR-378c controls VSMC dedifferentiation, proliferation, and SAMD1 expression, and also demonstrates that SAMD1/LDL binding leads to LDL oxidation and foam cell development [3]. Otherwise, SAMD1 has not been widely studied [4], and reports have primarily focused on roles in epigenetics:…”