Atherosclerosis is considered as a chronic inflammatory disease due to the infiltration of immune cells into lesions and the production of pro-inflammatory cytokines [20] , which contribute to the formation of vulnerable atherosclerotic plaques. Once infiltrated into the subendothelial space, some immune cells will unlimitedly take up lipids to continuously enlarge plaque [21] . The death of macrophage could induce plaque necrosis in advanced plaques, which may result in plaques instability and thus cause plaque rupture. Therefore, strategies to prevent macrophages apoptosis may stabilize the vulnerable plaques and reduce the life-threatening complications [21] . In addition, the interplays among immune cells, endothelial cells, platelets and smooth muscle cells facilitate the progression of the atherosclerotic plaques [22] [23] .

MicroRNAs are emerging as a new type of inflammatory regulators during atherosclerosis progression. Among them, let-7g was regarded to target inflammatory molecules. Let-7g, as an endogenous inhibitor of endothelial inflammatory activation, exerts a critical role in protecting endothelial cells [24] and sta- bling of atherosclerotic plaques. Let-7g leads to beneficial effects on EC through modulating TGF-β signaling and SIRT-1 signaling (Figure 2) [24] , which might contribute to the limitation of local inflammation of plaque and improve vascular thrombosis. In addition, overexpression of let-7g has resulted in the reduction of adhesion and migration of monocytes across endothelium [25] .

Macrophages are important inflammation cells in the formation of vulnerable plaque. Anti-inflammatory M2 macrophages help to stabilize atherosclerotic plaques [26] . Our research found that the relative expression levels of let-7g in different macrophages were different. After macrophages phagocytized ox-LDL, the relative expression levels of let-7g changed. So, we hypothesized that let-7g has a regulatory effect on macrophages in atherosclerotic plaques, and the specific regulatory mechanisms need to be further studied. Currently, what is the role of Let-7g in macrophage polarization during atherosclerosis remains largely unknown. This could be a new field of research in atherosclerosis in the near future.

In addition to inflammation, the status of extracellular matrix (ECM) of arteries is germane to the stabilization of atherosclerotic plaques. Plaques with high coll-

agen levels are more stable than plaques containing lower amounts of ECM protein [27] . The stabilization of atherosclerotic plaque depends on the content of ECM or collagen, the thickness of fibrous cap, the levels of proteases especially matrix metalloproteinases (MMPs) [1] .

MMPs is one big family of calcium-dependent, zinc-containing endopeptidases and often produced by inflammatory cells, such as foam cells and macrophages, within atherosclerotic plaques. MMPs have strong ability to remodel the extracellular matrix components [28] [29] [30] . It could digest extracellular matrix, which is beneficial to immigration of VSMC from the original site to the fiber cap, reduce the thickness of fibrous cap, and thus promote plaque rupture [31] . Johnson et al. [32] showed that a specific MMP-12 inhibitor could retard the development of atherosclerosis and increase fibrosis within the plaque in an atherosclerotic mouse model. Also, it was found that patients with carotid atherosclerosis had markedly increased levels of MMP-7 in plasma, especially whom with newly diagnosed symptoms [33] . Silencing MMP-9 by RNA interference in the mice arteries had been shown to increase the thickness of the fibrous cap [34] . The secretion of MMPs, mainly MMP-2 and MMP-9 by macrophages in plaque, has been associated with the vulnerable atherosclerotic plaque rupture [35] . Other numerous reports have shown that MMP-9 could induce monocyte/ macrophage differentiation, which resulted in progression and destabilization of atherosclerotic plaque [36] [37] [38] .

Although MMPs have been considered as a negative player in atherosclerotic plaque formation, it could act positively in the maintenance of atherosclerotic plaque stability on other aspects. Some reports suggested that MMP-2, MMP-9, and MMP-14 promoted migration and proliferation of VSMCs, which could increase fibrous cap thickness and maintain plaque stability [3] [39] . Therefore, MMPs seem to act as double-edged sword in plaque stabilization due to their different characteristics.

At present, although little is known about the effect of let-7g on MMPs in atherosclerosis, let-7g has been shown to suppress the expression and activity of MMP-2/-9 in breast cancer [40] , which indicates that let-7g may also contribute to the development of atherosclerotic plaque by regulating MMPs. Since MMPs might induce plaque rupture, it is possible that down-regulation of let-7g in susceptible individuals may increase MMPs effects and thus promote formation of unstable lesions [17] . In addition, different MMPs have differential effects on plaque stabilization. Which one is dominant becomes an issue of concern. The intriguing relationship between let-7g and MMPs on plaque stabilization is worth to further investigation.

Apoptosis of endothelial cells (ECs) and VSMCs could also influence stability of plaque. OxLDL, usually expressed higher in hyperlipidemia patients, has the toxicity effect on vascular endothelial cells, induced EC apoptosis through mitochondrial and death receptor (Fas/FasL) apoptotic pathways [41] , which is associated with thin and incomplete of fibrous cap. VSMCs, the main structure of artery medium layer, also play a significant role on the formation of advanced stage of atherosclerosis. Apoptosis of VSMCs is harmful to the stability of atherosclerosis plaque [42] . Therefore, maintenance of VSMCs has potential to delay the progression of atherosclerosis [31] .

It is well known that CASP3 is the major executioner caspase in apoptosis, and involves in cell cycle control, migration, and differentiation [43] [44] . Targeting CASP3 by hsa-let-7g significantly decreases apoptosis of endothelial cells induced by the ox-LDL. Hence, let-7g may have a significant influence on regulating ox-LDL-induced apoptosis and atherosclerosis [43] [45] . Report from Zhang group also suggested that overexpression of let-7g suppressed CASP3 expression and reduced apoptosis of ECs and the decreased levels of let-7g were found in apoptotic ECs elicited by ox-LDL [46] . As to VSMCs, observations from Ding group suggested that hsa-let-7g acts as a critical regulator of autophagy and apoptosis by modulating oxidized low density lipoprotein (lection- like) receptor 1 (LOX-1, aka. OLR1). Hsa-let-7g can reduce SMC apoptosis th- rough down-regulating cytochrome c and Smac/Diablo and up-regulating Bcl- xL and Bcl-2 expression [47] . Moreover, let-7g can down-regulate LOX-1 expression in a dose-dependent and time-dependent manner. Together, these studies indicate let-7g can suppress apoptosis and promote cell survival by negatively regulating LOX-1 expression [48] [49] or other pathways (Figure 3).

Current data suggest that let-7g is an important regulator of apoptosis of ECs and SMCs. Let-7g could also regulate other cellular apoptosis contributed to atherosclerosis. Thus it might be a potential target for therapeutic intervention. Insights into the regulation of let-7g in atherosclerosis-related apoptosis might guide to the development of an alternative strategy by targeting let-7g in treatment of disease characterized by LOX-1 over-expression such as atherosclerosis [46] .

Plaque angiogenesis is a physiological response to the increased oxygen demand in the plaque, which has adverse effects on plaque vulnerability. Neovessels in plaques are usually fragility which allows for extravasation of lipoproteins. How- ever, they can also promote the formation and enlargement of plaque lipid nucleus by letting red blood cells enter plaques, and results in plaque destabilization by increasing intraplaque hemorrhage and the infiltration of inflammatory cells [50] [51] [52] . Numerous studies have demonstrated that the co-existance of inflammatory and hypoxia in the plaque is a major stimulus for neovascularization [50] [51] [52] [53] . Indeed, it has been found that elevated oxygen tension could reduce hypoxia and inhibit the neovascularization of plaque and the progression lesion in mice [54] . Also, the inhibition of the lipid-driven inflammation or mo- nocyte influx has similar results [55] . Therefore, atherosclerosis promotes the development of angiogenesis, which in return accelerates the progression of pla- ques. Therefore, the inhibition of intraplaque angiogenesis seems to be especially important to increase the stability of plaque. From this point, anti-angiogenic substances have been considered as apotential targeted therapy to stable plaques [17] [56] .

Various miRNAs are associated with angiogenesis during different stages of atherosclerosis. According to published studies, let-7, miR-126, −143/145, −155, −17−92 and −222/221 could regulate angiogenesis [57] [58] [59] [60] [61] . Among them, the effects of let-7 on angiogenesis were firstly found by the knockdown of Dicer and Drosha in mouse which reduced let-7a, let-7b, let-7c, let-7f and let-7gmore than 30%. On the other hand, the reduction of let-7a, let-7b and let-7f has been verified to contribute to the sprouting of microvessels [62] [63] [64] . Recently, let-7g was shown to decrease angiogenesis and increase EC inflammation and monocyte adhesion via alterations in the TGF-β signaling pathway. Liao’s study suggested that venous injection of let-7g inhibitor into apolipoprotein E knockout mice increased the growth of vessels, the expression of PAI-1, and promoted the macrophage infiltration. At the same time, the up-regulations of TGF-β downstream genes were detected in the carotid arteries, and suppression of the TGF-β signaling by siRNAs could recover the angiogenesis [24] . Frangogiannis found that let-7g down-regulates expression of thrombospondin (TSP)-1, a matricellular protein with potent direct angiostatic properties [65] [66] . Thus, its impact on collateral circulation remains to be further investigated. These evidences indicate that let-7g plays important roles in plaque angiogenesis, but the underlie mechanism is complex and needs further studies.