Vascular remodeling stands for structural changes of the vessel wall in response to various noxious stimuli, which results in reorganization of the vessel wall architecture. Luminal narrowing because ...of neointima formation and constrictive remodeling leading to hypoperfusion is the most relevant clinical effect. Smooth muscle cell (SMC) accumulation, inflammatory cell recruitment, and endothelial regeneration are the critical parts in obstructive vascular remodeling. Chemokines and chemokine receptors have a great impact on initiating and progressing neointimal formation by controlling each step of the remodeling process. SDF-1alpha regulates vascular repair by CXCR4-dependent smooth muscle progenitor cell recruitment, which contributes to the maladaptive response to injury. The three distinct chemokine-chemokine receptor pairs MCP-1/CCR2, RANTES/CCR5, and Fractalkine/CX(3)CR1 direct lesional leukocyte infiltration. In addition MCP-1/CCR2 and Fractalkine/CX(3)CR1 increase neointimal SMC expansion. In contrast, KC/Gro-alpha supports endothelial recovery through CXCR2, which attenuates neointima formation. These findings highlight the importance to characterize specific functions of the chemokine network to enable therapeutic intervention.
Macrophages play a crucial role in the innate immune system and contribute to a broad spectrum of pathologies, like in the defence against infectious agents, in inflammation resolution, and wound ...repair. In the past several years, microRNAs (miRNAs) have been demonstrated to play important roles in immune diseases by regulating macrophage functions. In this review, we will summarize the role of miRNAs in the differentiation of monocytes into macrophages, in the classical and alternative activation of macrophages, and in the regulation of phagocytosis and apoptosis. Notably, miRNAs preferentially target genes related to the cellular cholesterol metabolism, which is of key importance for the inflammatory activation and phagocytic activity of macrophages. miRNAs functionally link various mechanisms involved in macrophage activation and contribute to initiation and resolution of inflammation. miRNAs represent promising diagnostic and therapeutic targets in different conditions, such as infectious diseases, atherosclerosis, and cancer.
The maladaptation of endothelial cells to disturbed flow at arterial bifurcations increases permeability for lipoproteins. Additional injury by chemically modified lipoproteins disrupts the ...continuous repair of maladapted endothelial cells and triggers intimal macrophage accumulation. Macrophages remove modified lipoproteins from the extracellular space until the cholesterol overload leads to macrophage death and insufficient efferocytosis. This macrophage failure promotes the progression to advanced lesions by formation of a lipid-rich necrotic core, which may rupture and cause myocardial infarction and stroke. In this article, we summarize the fundamental roles of microRNAs (miRNAs) in the regulation of endothelial maladaptation and macrophage failure during atherosclerosis. We describe how miRNAs coordinate the mutual interaction between chronic endothelial repair and endothelial senescence and mechanistically link the regulation of macrophage cholesterol homeostasis with defective efferocytosis. Lastly, we discuss how miRNAs may challenge and extend current theories about atherosclerosis.
Lysophosphatidic acid (LPA) is a potent bioactive phospholipid. As many other biological active lipids, LPA is an autacoid: it is formed locally on demand, and it acts locally near its site of ...synthesis. LPA has a plethora of biological activities on blood cells (platelets, monocytes) and cells of the vessel wall (endothelial cells, smooth muscle cells, macrophages) that are all key players in atherosclerotic and atherothrombotic processes. The specific cellular actions of LPA are determined by its multifaceted molecular structures, the expression of multiple G‐protein coupled LPA receptors at the cell surface and their diverse coupling to intracellular signalling pathways. Numerous studies have now shown that LPA has thrombogenic and atherogenic actions. Here, we aim to provide a comprehensive, yet concise, thoughtful and critical review of this exciting research area and to pinpoint potential pharmacological targets for inhibiting thrombogenic and atherogenic activities of LPA. We hope that the review will serve to accelerate knowledge of basic and clinical science, and to foster drug development in the field of LPA and atherosclerotic/atherothrombotic diseases.
Chemokines and microRNAs in atherosclerosis Hartmann, Petra; Schober, Andreas; Weber, Christian
Cellular and Molecular Life Sciences,
09/2015, Volume:
72, Issue:
17
Journal Article, Book Review
Peer reviewed
Open access
The crucial role of chemokines in the initiation and progression of atherosclerosis has been widely recognized. Through essential functions in leukocyte recruitment, chemokines govern the ...infiltration with mononuclear cells and macrophage accumulation in atherosclerotic lesions. Beyond recruitment, chemokines also provide homeostatic functions supporting cell survival and mediating the mobilization and homing of progenitor cells. As a new regulatory layer, several microRNAs (miRNAs) have been found to modulate the function of endothelial cells (ECs), smooth muscle cells and macrophages by controlling the expression levels of chemokines and thereby affecting different stages in the progression of atherosclerosis. For instance, the expression of CXCL1 can be down-regulated by miR-181b, which inhibits nuclear factor-κB activation in atherosclerotic endothelium, thus attenuating the adhesive properties of ECs and exerting early atheroprotective effects. Conversely, CXCL12 expression can be induced by miR-126 in ECs through an auto-amplifying feedback loop to facilitate endothelial regeneration, thus limiting atherosclerosis and mediating plaque stabilization. In contrast, miR-155 plays a pro-atherogenic role by promoting the expression of CCL2 in M1-type macrophages, thereby enhancing vascular inflammation. Herein, we will review novel aspects of chemokines and their regulation by miRNAs during atherogenesis. Understanding the complex cross-talk of miRNAs controlling chemokine expression may open novel therapeutic options to treat atherosclerosis.
Atherosclerosis is characterised by the accumulation of lipid-laden macrophages in atherosclerotic lesions and occurs preferentially at arterial branching points, which are prone to inflammation ...during hyperlipidaemic stress. The increased susceptibility at branching sites of arteries is attributable to poor adaptation of arterial endothelial cells to disturbed blood flow. In the past 5 years, several studies have provided mechanistic insights into the regulatory roles of microRNAs (miRNAs) in inflammatory activation, proliferation, and regeneration of endothelial cells during this maladaptive process. The intercellular transfer of vesicle-bound miRNAs contributes to arterial homeostasis, and the combinatorial effect of multiple miRNAs controls the unresolved inflammation orchestrated by macrophages in atherosclerotic lesions. In this Review, we highlight the miRNA-dependent regulation of the endothelial phenotype and the proliferative reserve that occurs in response to altered haemodynamic conditions as a prerequisite for atherogenic inflammation. In particular, we discuss the regulation of transcriptional modules by miRNAs and the protective role of complementary strand pairs, which encompasses remote miRNA signalling. In addition, we review the roles of miRNA tandems and describe the relevance of RNA target selection and competition to the behaviour of lesional macrophages. Elucidating miRNA-mediated regulatory mechanisms can aid the development of novel diagnostic and therapeutic strategies for atherosclerosis.
A number of cardiovascular diseases, such as restenosis, aneurysm, and atherosclerosis, lead to vascular remodeling associated with complex adaptive reactions of different cell populations. These ...reactions include growth of smooth muscle cells, proliferation of endothelial cells, and the inflammatory response of macrophages. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease by post-transcriptional regulation of gene expression. Here, we review the molecular mechanisms of a subset of miRNAs involved in vascular remodeling, including miR-143/145, miR-221/222, miR-126, miR-21, and miR-155. Some of these miRNAs, such as miR-143/145 and miR-126, have been shown to be protective during vascular remodeling, whereas others, such as miR-21, may promote the cellular response that leads to neointima formation. The increasing knowledge regarding the roles of miRNAs in vascular remodeling opens novel avenues for the treatment of various cardiovascular diseases. However, more in vivo studies on the functional roles of these miRNAs are required in the future.
Macrophages in atherosclerotic plaques drive inflammatory responses, degrade lipoproteins, and phagocytose dead cells. MicroRNAs (miRs) control the differentiation and activity of macrophages by ...regulating the signaling of key transcription factors. However, the functional role of macrophage-related miRs in the immune response during atherogenesis is unknown. Here, we report that miR-155 is specifically expressed in atherosclerotic plaques and proinflammatory macrophages, where it was induced by treatment with mildly oxidized LDL (moxLDL) and IFN-γ. Leukocyte-specific Mir155 deficiency reduced plaque size and number of lesional macrophages after partial carotid ligation in atherosclerotic (Apoe-/-) mice. In macrophages stimulated with moxLDL/IFN-γ in vitro, and in lesional macrophages, loss of Mir155 reduced the expression of the chemokine CCL2, which promotes the recruitment of monocytes to atherosclerotic plaques. Additionally, we found that miR-155 directly repressed expression of BCL6, a transcription factor that attenuates proinflammatory NF-κB signaling. Silencing of Bcl6 in mice harboring Mir155-/- macrophages enhanced plaque formation and CCL2 expression. Taken together, these data demonstrated that miR-155 plays a key role in atherogenic programming of macrophages to sustain and enhance vascular inflammation.
Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. ...Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126(-/-) mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126(-/-) mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach.
Macrophages play a crucial role in the innate immune system and contribute to a broad spectrum of pathologies in chronic inflammatory diseases. MicroRNAs (miRNAs) have been demonstrated to play ...important roles in macrophage functions by regulating macrophage polarization, lipid metabolism and so on. Thus, miRNAs represent promising diagnostic and therapeutic targets in immune disorders. In this review, we will summarize the role of miRNAs in atherosclerosis, metabolic syndrome, and cancer by modulating macrophage phenotypes, which has been supported by in vivo evidence.
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