Cardiovascular Research

Cardiovascular Research Advance Access first published online on June 11, 2008
This version [Corrected Proof] published online on July 1, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn156

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Role of microRNAs in vascular diseases, inflammation, and angiogenesis

Carmen Urbich, Angelika Kuehbacher and Stefanie Dimmeler^*

Department of Molecular Cardiology, Internal Medicine III, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany

^* Corresponding author. +49 69 6301 7440; fax: +49 69 6301 7113. E-mail address: dimmeler{at}em.uni-frankfurt.de

Received 18 March 2008; revised 20 May 2008; accepted 4 June 2008

Time for primary review: 26 days

	Abstract

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
The integrity of the endothelial monolayer is fundamental for the homoeostasis of the vascular system. Functional endothelial cells are also required for the growth of new blood vessels during neovascularization. Although multiple growth factors have been shown to regulate angiogenesis and vascular development, little is known about the complex upstream regulation of gene expression and translation. MicroRNAs (miRNAs) are an emerging class of highly conserved, non-coding small RNAs that regulate gene expression on the post-transcriptional level by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA. More than 500 human miRNAs have been identified so far, and increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in various physiological and pathological processes such as cardiogenesis, haematopoietic lineage differentiation, and oncogenesis. Meanwhile, a few specific miRNAs that regulate endothelial cell functions and angiogenesis have been described. Let7-f, miR-27b, and mir-130a were identified as pro-angiogenic miRNAs. In contrast, miR-221 and miR-222 inhibit endothelial cell migration, proliferation, and angiogenesis in vitro by targeting the stem cell factor receptor c-kit and indirectly regulating endothelial nitric oxide synthase expression. Moreover, some miRNAs are involved in tumour angiogenesis such as the miR-17-92 cluster and miR-378. Early studies also indicate the contribution of specific miRNAs (e.g. miR-155, miR-21, and miR-126) to vascular inflammation and diseases. Thus, the identification of miRNAs and their respective targets may offer new therapeutic strategies to treat vascular diseases such as atherosclerosis, to improve neovascularization after ischaemia, or to prevent tumour progression.

KEYWORDS MicroRNA; Angiogenesis; Endothelial cells; Gene expression; Vascular diseases

	1. Introduction

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
The functionality of endothelial cells is fundamental for the homoeostasis of the vascular system. Due to its unique position in the vessel wall, the endothelium acts as a barrier and serves as the primary sensor of blood flow-mediated mechanotransduction. Hemodynamic forces provided by the flowing blood (‘shear stress’) exert atheroprotective functions and mediate vessel remodelling. Vascular remodelling is characterized by the reorganization of blood vessels in response to physiological or to pathophysiological stimuli. Functional endothelial cells are also required for angiogenesis, the growth of new blood vessels from pre-existing vessels, a process involving proliferation, migration, and maturation of endothelial cells. In addition, circulating progenitor cells home to sites of neovascularization and differentiate into endothelial cells in situ, thereby contributing to vasculogenesis.

The coordinated regulation of angiogenesis, vasculogenesis, and vessel regression is not only essential for the development of the vascular system but also for the maintenance of vascular function. Improvement of endothelial cell function, enhancement of angiogenesis after critical ischaemia, and inhibition of angiogenesis during tumour growth are of considerable interest as therapeutic strategies. However, little is known about the complex regulation of gene expression during neovascularization and vascular remodelling. MicroRNAs (miRNAs) are a recently recognized class of highly conserved, non-coding short RNA molecules (about 22 nt) that regulate gene expression on the post-transcriptional level. MiRNAs suppress protein synthesis by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA, thereby silencing gene expression. In the present review, we summarize the role of miRNAs and their respective targets for angiogenesis and vascular diseases and their potential applicability to treat cardiovascular diseases.

	2. MiRNA processing and mechanism of action

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
The transcription of miRNAs depends on their localization within the genome. miRNAs can be located in introns of coding genes or noncoding genes or in exons. Then the miRNA transcription depends on the host gene.^1,2 MiRNAs that have their own promoters are independently expressed, and miRNAs organized in clusters share the same transcriptional regulation.^3,4 Once the miRNAs are expressed, their maturation is mediated by the two RNase III endonucleases Dicer and Drosha (Figure 1; for review see⁵). The mature miRNA incorporates into the RNA-induced silencing complex (RISC),⁶ which directs the miRNA to the target mRNA leading either to translational repression or degradation of the target mRNA.⁵ Whereas mRNA degradation requires a high miRNA-target complementarity, the translational repression is characterized by low miRNA-target complementarity.⁷ It is estimated that about one-third of the genes are regulated by miRNAs. The complexity of miRNA-dependent gene expression is further extended by the fact that more than one miRNA can cooperatively bind to the same 3'UTR⁸ and that each miRNA can regulate hundreds of targets. In an even more complex manner, it has been for example shown that human miR-29b is predominantly localized to the nucleus as a result of its terminal hexanucleotide motif, suggesting that miRNAs may also regulate transcription or splicing of transcripts within the nucleus⁹ (Figure 1). In addition, exosomes mediate the transfer of miRNAs as a novel mechanism of genetic exchange between cells¹⁰ (Figure 1). Based on these findings, it will not be a surprise that miRNAs may be involved in almost every biological process.

View larger version (28K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 MiRNA biogenesis. The maturation of miRNAs is mediated by the two RNase III endonucleases Dicer and Drosha. In the first step, the microprocessor complex composed of Drosha and DGCR8 mediates the nuclear processing of the primary-miRNAs (pri-miRNA) into stem-loop precursors of approximately 60–70 nucleotides (pre-miRNA). The nuclear export of the precursors is subsequently mediated by exportin-5 in a Ran-GTP dependent manner. In the second step, the pre-miRNA is cleaved in the cytoplasm by Dicer into the mature 22 nucleotide miRNA, which incorporates as single-stranded RNA into the RNA-induced silencing complex (RISC). This complex directs the miRNA to the target mRNA, which leads either to translational repression or degradation of the target mRNA. MicroRNAs are also localized to the nucleus, where they may regulate transcription or splicing of transcripts. In addition, exosomes mediate the transfer of miRNAs.

 
Little is known about the upstream mechanisms that control miRNA abundance. The first level of regulation includes the miRNA transcription and processing. In this context, a tissue-specific regulation of pri-miRNA transcription has been demonstrated.^11–14 In matters of maturation, processing by Dicer can be delayed or inhibited.^15–17 To give an example, miR-138, which regulates human telomerase reverse transcriptase during the development of thyroid carcinoma,¹⁸ is spatially restricted to distinct cell types, while its precursor is ubiquitously expressed in different tissues.¹⁷ In addition, miRNAs can be suppressed as a consequence of the Drosha-processing block as it has been shown during early mouse development.¹⁹ Taken together, these findings indicate that miRNA function might be controlled by differential-processing mechanisms.

	3. Role of Dicer and Drosha for the cardiovascular system

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
Since Dicer is involved in the maturation of miRNAs and each miRNA has multiple downstream targets, one would expect a tremendous impact of Dicer for biological processes. Indeed, Dicer is essential for early mouse development.²⁰ During embryogenesis, Dicer is required for normal skeletal muscle development.²¹ Growing evidence also suggests an important role of Dicer for the cardiovascular system. Thus, the cardiac-specific deletion of Dicer results in defective heart development and embryonic lethality.²² Moreover, the postnatal cardiac-specific knockout of Dicer leads to dilated cardiomyopathy associated with heart failure²³ supporting the role of Dicer for cardiac development and function.

Recent data also indicate a role of Dicer for angiogenesis in vitro and in vivo. In embryonic development, Dicer-deficient mice die during mid-gestation between E12.5 and 14.5 showing an impaired blood vessel formation and yolk sac vascularization.²⁴ Consistently, zebrafish Dicer mutant embryos display disrupted blood circulation.²⁵ In endothelial cells, Dicer is constitutively expressed and silencing of Dicer in endothelial cells with siRNA oligonucleotides reduces the formation of capillary-like structures and proliferation.^26,27 In accordance, Dicer knockdown in human microvascular endothelial cells diminished cell migration and matrigel tube formation.²⁸ The analysis of the molecular mechanism of Dicer-dependent regulation of angiogenesis revealed, as expected, an alteration of gene expression in response to Dicer knockdown. Two studies demonstrated a profound dysregulation of angiogenesis-related genes in vitro and in vivo after Dicer knockdown.^26,27 Surprisingly, critical regulators of angiogenesis such as vascular endothelial growth factor (VEGF) and its receptor Flt1 were upregulated after Dicer depletion.^26,27 The VEGF-R2 (KDR) was upregulated in one study²⁶ but was not affected in another study,²⁷ which might suggest that this regulation is a highly dynamic process. Furthermore, protein levels of Tie-1 are decreased in Dicer ^ex1/2 embryos,²⁴ whereas its expression is strongly enhanced in Dicer-depleted cultured endothelial cells,²⁶ indicating that different miRNAs are spatiotemporally expressed during development compared with isolated endothelial cells in culture. In addition to angiogenesis-related genes, Dicer also interferes with redox signalling in endothelial cells.²⁸ Thus, Dicer knockdown reduces the expression of miRNAs that control the expression of the HMG-box protein 1 (HBP1) transcriptional suppressor, which negatively regulates p47phox of the NADPH oxidase complex. Given that levels of reactive oxygen species are elevated in hypertension, diabetes, and atherosclerosis,^29,30 one could imagine an important role of Dicer in vascular diseases.

In contrast to Dicer less is known about the biological effects of Drosha for vascular biology. In vitro experiments demonstrated that treatment of Hela cells with RNA interference against Drosha results in the strong accumulation of pri-miRNAs and the reduction of pre-miRNAs and mature miRNAs.³¹ However, the effect of Drosha on endothelial cell function and angiogenesis is less pronounced as opposed to Dicer.²⁷ Although genetic silencing of Drosha in endothelial cells with siRNA significantly impairs capillary-sprouting and tube-forming activities, depletion of Drosha does not exert significant effects on in vivo angiogenesis in a matrigel plug model.²⁷

	4. Role of specific miRNAs for endothelial cell function and angiogenesis

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
There is an increasing evidence that specific miRNAs are involved in various biological processes such as cardiogenesis, skeletal muscle proliferation and differentiation, brain morphogenesis, oncogenesis, and haematopoietic lineage differentiation.^{12,13,25,32,33} While the function of Dicer and Drosha for angiogenesis is partially addressed (see the above section), the role of specific miRNA in vascular and endothelial cell biology is currently limited.

4.1 Pro-angiogenic miRNAs
One important characteristic of miRNA expression is the tissue- and cell-type-specific expression pattern. miRNA profiles of endothelial cells revealed that specific miRNAs are enriched in endothelial cells including among others let-7b, miR-16, miR-21, miR-23a, miR-29, miR-100, miR-221, and miR-222.^26,27,34 In addition, miR-126 is enriched in embryonic bodies-derived Flk-1⁺ cells.³⁵ Most of these miRNAs were also highly expressed in normal rat carotid arteries,³⁶ suggesting that these miRNAs indeed belong to the specific miRNA signature of the vasculature. With regard to angiogenesis, the highly expressed let-7f and miR-27b exert pro-angiogenic effects as evidenced by the blockade of in vitro angiogenesis with 2'-O-methyl oligonucleotide inhibitors²⁷ (Table 1).

View this table: [in this window] [in a new window]   Table 1 Summary of microRNAs involved in vascular biology

 
However, one should not only focus on highly expressed miRNAs in endothelial cells, because miRNAs expressed on a lower level under physiological conditions might be upregulated under certain conditions (e.g. after angiogenic activation). So far little is known about the impact of hypoxia, inflammation, cardiovascular risk factors, or laminar shear stress on the expression profile of miRNAs in vascular cells. The elucidation of the regulation of miRNAs during pathophysiological processes may uncover further insights in the role of miRNAs in vascular cells. Two recent studies investigated the regulation of miRNAs in vascular cells in response to serum and hypoxia, respectively. Thus, the pro-angiogenic miR-130a is expressed at low levels in quiescent HUVEC and is upregulated in response to foetal bovine serum.³⁷ miR-130a downregulates the anti-angiogenic homeobox proteins GAX (growth arrest homeobox) and HoxA5, and functionally antagonized the inhibitory effects of GAX on endothelial cells proliferation, migration and tube formation and the inhibitory effects of HoxA5 on tube formation vitro³⁷ (Figure 2). miR-210 is induced by hypoxia in endothelial cells.³⁸ MiR-210 overexpression enhanced the formation of capillary-like structures and VEGF-driven migration of normoxic endothelial cells, whereas inhibition of miR-210 decreased tube formation and migration.³⁸ The modulation of endothelial cell responses to hypoxia is mediated via the regulation of the receptor tyrosine-kinase ligand EphrinA3³⁸ (Figure 2). Of note, miRNA profiles of cancer cells revealed that at least a subgroup of hypoxia-regulated miRNAs are induced by hypoxia inducible factor (HIF), supporting the key role of HIF as transcription factor for miRNA expression during hypoxia.³⁹ This finding might also be of importance to understand the regulation of miRNAs in vascular cells.

View larger version (59K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Role of miRNAs for vascular biology. Schematic illustration of the specific functions of miR-221/miR-222, miR-17-92, miR-210, miR-130a, and miR-126 for vascular biology.

 
4.2 Anti-angiogenic miRNAs
Among the highly expressed miRNAs in HUVEC, miR-221 and miR-222 exert anti-angiogenic effects³⁴ (Table 1). Thus, transfection of endothelial cells with miR-221 and miR-222 inhibits tube formation, migration, and wound healing of endothelial cells in vitro.³⁴ Consistently, another study demonstrated the anti-angiogenic function of miR-221/222 in endothelial cells.²⁶ The underlying mechanism involves the downregulation of the protein expression of the predicted target c-kit, the receptor for stem cell factor, without affecting the mRNA level, suggesting a posttranscriptional regulation.³⁴ In haematopoietic progenitor cells, the miR-221/222 family also reduces c-kit expression and as a functional consequence cell proliferation.⁴⁰ Because c-kit is an important marker of cardiac stem cells^41,42 it is tempting to speculate that miR-221 and miR-222 might also be involved in cardiac stem cell differentiation or function. However, the role of miR-221 and miR-222 for cardiac function or differentiation has not been described so far. MiR-221 and miR-222 overexpression also indirectly reduces the expression of the endothelial nitric oxide synthase (eNOS) in Dicer siRNA-transfected cells.²⁶ Nitric oxide (NO) is not only a key regulator for endothelial cell growth,⁴³ migration,⁴⁴ vascular remodelling,⁴⁵ and angiogenesis,⁴⁶ its impaired bioavailability is also a hallmark of patients with atherosclerosis and ischaemic cardiomyopathy.⁴⁷ Importantly, it was recently demonstrated that eNOS plays also a crucial role for the mobilization and functional activity of stem and progenitor cells.^48–50 Thus, miRNAs targeting eNOS might not only regulate angiogenesis as it has been shown for miR-221/222, but might also be involved in vasculogenesis (Figure 2).

Depletion of miR-221 and miR-222 also changed the miRNA signature of HUVEC⁵¹ indicating that miRNAs control the expression of other miRNAs. Nine miRNAs were upregulated and 23 miRNAs were downregulated in response to miR-221/222 depletion. Interestingly, one-third of the regulated miRNAs are predicted to target c-kit 3'UTR, suggesting a connection between miRNAs that share similar functions. However, the mechanism how miRNAs regulate miRNAs is not resolved, but might be explained by the interference with the expression or activity of the miRNA-processing machinery or the involvement of transcription factors, which in turn control miRNA expression.⁵¹ Indeed, recent data demonstrated that the transcription factor Myc can activate or repress different sets of miRNAs.⁵²

4.3 Tumour angiogenesis
Recent insights suggest that cancer therapy will comprise a combination of anti-angiogenic agents (e.g. VEGF inhibitors) and cytotoxic chemotherapy targeting tumour cells. Therefore, the identification of miRNAs regulating both angiogenesis and tumour cell survival is a meaningful approach for the therapy of cancer. On the basis of the findings that miR-221 and miR-222 target at least two important regulators of pro-angiogenic endothelial cell function, it might be an attractive tool to block angiogenesis.

A potent tumour angiogenesis-promoting activity has been shown for the miRNA cluster miR-17-92, consisting of miR-17, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92a.⁵³ The miR-17-92 cluster is significantly up-regulated in Myc-induced tumours and overexpression of miR-17-92 in Ras cells enhances tumour vessel growth in a paracrine manner. When expressed in tumour cells, members of the miR-17-92 cluster specifically target anti-angiogenic proteins.⁵⁴ In particular, miR-18 preferentially suppresses connective tissue growth factor (CTGF) expression, whereas miR-19 targets the potent angiogenesis-inhibitor thrombospondin-1 (TSP-1)⁵⁴ (Figure 2). The function of the miR-17-92 cluster in endothelial cells and the specific role of the individual miRNAs remains to be determined.

MiR-378 also enhances tumour angiogenesis, tumour cell survival, and growth by targeting the tumour suppressors SuFu (suppressor of fused) and Fus-1 (tumour suppressor candidate 2 TUSC2).⁵⁵ Similarly, a broad effect has been demonstrated for miR-15 and miR-16, which are both downregulated by hypoxia in a carcinoma cell line and regulate the expression of VEGF.⁵⁶ Thus, miR-15 and miR-16 induce apoptosis of leukaemic cells by targeting the anti-apoptotic protein Bcl-2, block cell cycle progression and are frequently downregulated in chronic lymphocytic leukaemia.^57,58

In summary, the identification of miRNAs with a dual anti-tumour and anti-angiogenic effect may provide powerful anti-cancer drugs. Because of their broad function during tumourigenesis, regulating miR-378 and miR-15/16 might be an attractive anti-tumour strategy. However, their value to cancer therapy remains to be established. One promising approach for initial animal experiments is the systemic application of antagomirs that are single-stranded RNA oligonucleotides complementary to specific miRNAs with chemical modification for stability and cholesterol conjugation for better delivery that are well suited to block miRNA functions in small-animal models.^59,60

	5. Role of specific miRNAs for vascular diseases

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
Inflammation is an important part of host defences against infection and injury, but it is also thought to contribute to multiple acute and chronic diseases such as ischaemia/reperfusion damage and atherosclerosis.^61,62 Atherosclerosis is meanwhile established as an chronic inflammatory disease.⁶¹ The response-to-injury hypothesis describes that endothelial dysfunction caused by, for example, elevated LDL, free radicals, hypertension, diabetes mellitus, and/or other factors is an early step in atherosclerosis. Thus, during the initiation of atherosclerosis leading to the formation of atherosclerotic lesions, different forms of injury increase endothelial permeability and adhesiveness via upregulation of leukocyte adhesion molecules (e.g. L-selectin, integrins, and platelet–endothelial–cell adhesion molecule 1) and endothelial adhesion molecules (e.g. E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1). Leukocytes then adhere to the activated endothelium and migrate into the artery wall. During progression of atherosclerosis fatty-streaks were formed consisting of lipid-laden macrophages (foam cells) and T lymphocytes, which release proteases, cytokines, chemokines, and growth factors. Platelets adhere and aggregate. In addition, smooth-muscle cells migrate and proliferate within the intermediate lesion. This lead to further expansion of the lesion, which may end up in advanced, complicated lesions followed by complications such as plaque rupture and thrombosis.

Because miRNAs are upstream regulators of gene expression and are involved in various physiological and pathological processes, it would be needful to address their role in vascular inflammation, in particular in leukocyte activation and their infiltration into the vascular wall. Indeed, a recent study provides first evidence that miRNAs control vascular inflammation.⁶³ miR-126 inhibited the expression of vascular cell adhesion molecule 1 (VCAM-1), which mediates leukocyte adherence to endothelial cells (Figure 2). Thus, decreasing miR-126 in endothelial cells increases TNF-stimulated VCAM-1 expression and enhances leukocyte adherence to endothelial cells.⁶³ Recently, it has been shown that miR-21 is a regulator of neointima lesion formation³⁶ (Table 1). Thus, downregulation of aberrantly expressed miR-21 decreased neointima formation in rat carotid artery after angioplasty. Western blot analysis indicates that PTEN and Bcl-2 are involved in miR-21-dependent proliferation and apoptosis of VSMC. Another study demonstrates that the angiotensin II type 1 receptor (AT1R) and miR-155 are co-expressed in endothelial cells and vascular smooth-muscle cells and that miR-155 translationally represses the expression of AT1R.⁶⁴ A silent polymorphism (+1166 A/C) in the human AT1R has been associated with cardiovascular disease, probably mediated by enhanced AT1R activity. Interestingly, the presence of the +1166 C-allele interrupts base-pairing complementarity within the 3'UTR of AT1R, and, thereby, decreases translational repression of AT1R by miR-155.⁶⁴ In addition, stimulation of fibroblasts with transforming growth factor-beta 1 decreased the expression of miR-155 and increased the expression of the human AT1R, demonstrating the physiological regulation of miR-155.⁶⁵ miR-155 is induced in macrophages by cytokines such as TNF and IFN-beta^66,67 and contributes to physiological granulocyte/monocyte expansion during inflammation.⁶⁸ In addition, miR-155 is required for B and T lymphocyte and dendritic cell function.^69,70 Mechanistically, the transcription factor Pu.1 has been identified as a direct target of miR-155 in B cells.⁷⁰ Thus, miR-155 is an emerging target of a broad range of inflammatory mediators and regulates lymphoid and myeloid cell functions.

Although only a few studies assessed the direct role of miRNAs for vascular inflammation and diseases, several studies addressed the contribution of miRNAs for the differentiation and function of haematopoietic cells involved in inflammation. Since inflammation is clearly a key event for the initiation and progression of atherosclerotic lesion formation, miRNA-dependent regulation of inflammatory cells may be involved in the control of vascular inflammation and atherosclerosis. A study by Chen and coworkers was one of the first studies demonstrating that miRNAs, in particular miR-181, regulate haematopoietic lineage differentiation.³² Furthermore, several miRNAs regulate B-cell differentiation, including the miR-17-92 cluster and miR-150.^71–73 Overexpression of the miR-17-92 cluster in lymphocytes additionally induces lymphoproliferative disease and autoimmunity.⁷⁴

MiRNAs also modulate monocyte differentiation and function. During monocyte differentiation, the transcription factor PU.1 activates the transcription of miR-424 that represses the translation of the transcription factor NFI-A. The inhibition of NFI-A in turn allows the activation of the differentiation-specific gene M-CSF receptor, thus controlling monocyte/macrophage differentiation.⁷⁵ Moreover, miR-17-5p-20a-106a control monocytopoiesis through regulation of AML1 and M-CSF receptor⁷⁶ and miR-146 is induced in macrophages by several microbial components and proinflammatory cytokines in an NF-kappaB-dependent manner.⁷⁷ Finally, the myeloid-specific miR-223 regulates progenitor proliferation and granulocyte differentiation and activation during inflammation.⁷⁸

Taken together, miR-21, miR-155, and miR-126 might be important modulators of vascular disease and vessel remodelling. In addition, the miR-17-92 cluster and miR-150 regulating B cell development as well as miR-424, miR-17-5p-20a-106a, and miR-146 regulating monocyte/macrophage differentiation are interesting candidates, which may be involved in inflammatory responses during various cardiovascular diseases. The potential contribution of miRNAs during atherogenesis is summarized in Figure 2. However, further studies are required to address the contribution of specific miRNAs for vascular inflammation.

	6. Conclusion

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
In summary, miRNAs are intimately involved in vascular biology. Although >500 miRNAs have been discovered in mammalian genomes, for many miRNAs the nature of the target transcripts is unknown. Meanwhile, open-source software is available for miRNA target prediction using different algorithms (e.g. miRanda, PicTar, and MiRBase). The algorithms might facilitate the identification of predicted target sites on the 3' untranslated regions of human gene transcripts for currently known mammalian miRNAs based on interspecies conservation. In order to use miRNAs as therapeutical tools the complete spectrum of miRNA targets in different tissues needs to be specified in detail. So far only a few studies have explicitly shown a direct regulation of the predicted target in endothelial cells (e.g. the regulation of Gax by miR-130a). Hopefully additional targets will be discovered in future studies. Limited information is also available regarding the function of specific miRNAs in vascular cells. Recently, miR-21, miR-155, and miR-126 have been implicated in vascular diseases and inflammation. Moreover, a few miRNAs are involved in endothelial cell functions or in (tumour) angiogenesis (e.g. miR-221/222, miR-130a, miR-378, miR-17-92, miR-27b, and let-7f; Figure 2). Understanding the complex network involving miRNAs and their targets leading to a coordinated pattern of gene expression undoubtedly will provide important tools to develop novel therapeutic strategies not only to enhance neovascularization of ischaemic tissue but also to interfere with dysregulated vascular remodelling, the key mechanism for atherosclerotic disease progression. In addition, selective regulation of particular miRNAs targeting tumour cell survival and tumour angiogenesis is a promising prospect as a candidate for tumour therapy.

Conflict of interest: none declared.

	Funding

Top Abstract 1. Introduction 2. MiRNA processing and... 3. Role of Dicer... 4. Role of specific... 5. Role of specific... 6. Conclusion Funding References

 
Our work was supported by the Excellence Cluster Exc 147/1 by the DFG (German Research Foundation).

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