MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo

Cui, Rongrong; Li, Shijun; Liu, Lingjuan; Lee, Yi; Liang, Qiu-Hua; Zhu, Xiao Feng; Liu, Guan-Ying; Liu, Yuan; Wu, Shanshan; Liao, Xiao‐Bo; Yuan, Ling‐Qing; Mao, Ding-An; Liao, Er-Yuan

doi:10.1093/cvr/cvs258

Cited by 145 publications

(146 citation statements)

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“…59 Interestingly, it was shown that RUNX2 is one of the most conserved predicted targets of miR-204 60 and is regulated by this miRNA in systemic vascular disease. 61 As expected, we documented that in vitro downregulation of miR-204 in healthy PASMCs results in RUNX2 and HIF-1α activation, while miR-204 upregulation in PAH-PASMC results in decreased RUNX2 and HIF-1α activation. 56,59 These effects are associated with decreases in both PASMC proliferation and apoptosis resistance in PAH.…”

Section: Molecular Contribution Of Pasmcs To Pah Phenotypesupporting

confidence: 85%

Vascular Remodeling Process in Pulmonary Arterial Hypertension, with Focus on miR‐204 and miR‐126 (2013 Grover Conference Series)

et al. 2014

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Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized primarily by increased proliferation and resistance to apoptosis in distal pulmonary arteries. Previous literature has demonstrated that the transcription factors NFAT (nuclear factor of activated T cells) and HIF-1α (hypoxia inducible factor 1α) are extensively involved in the pathogenesis of this disease and, more recently, has implicated STAT3 (signal transducer and activator of transcription 3) in their activation. Novel research shows that miR-204, a microRNA recently found to be notably downregulated through induction of PARP-1 (poly [ADP-ribose] polymerase 1) by excessive DNA damage in PAH, inhibits activation of STAT3. Contemporary research also indicates systemic impairment of skeletal muscle microcirculation in PAH and attributes this to a debilitated vascular endothelial growth factor pathway resulting from reduced miR-126 expression in endothelial cells. In this review, we focus on recent research implicating miR-204 and miR-126 in vascular remodeling processes, data that allow a better understanding of PAH molecular pathways and constitute a new hope for future therapy.Keywords: pulmonary arterial hypertension, microRNA, vascular remodeling, angiogenesis, skeletal muscle. Pulmonary arterial hypertension (PAH) is a severe disorder clinically defined by mean pulmonary arterial pressure of at least 25 mmHg at rest. 1 PAH patients display multiple symptoms that are not specific to PAH, including dyspnea, dizziness, and exercise intolerance. Mean age at diagnosis is around 45 years, although onset of symptoms can occur at any age. 2 Epidemiologically, it is estimated that between 20 and 50 persons per million suffer from this disease. 3 Physiologically, PAH is a vascular remodeling disease of various degrees that affects the adventitia, media, and intima of distal pulmonary arteries, leading to decreased lung perfusion and sustained elevation of pulmonary vascular resistance. 4 In response to this resistance, patients develop progressive compensatory right ventricular hypertrophy, which rapidly becomes insufficient and leads to dilatation and failure. 5,6 Histologically, PAH is associated with enhanced inflammation, proliferation, and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). 7 Despite progress in treatment, medication remains limited and noncurative, and therefore PAH patients typically have poor prognoses (mortality rate of more than 10% after the first year of therapy) 8 and quality of life remains severely affected. The pathological mechanisms of PAH establishment need to be better understood and further studied because of their complexities and therapeutic interest. Indeed, knowledge regarding the molecular actors implicated in these impairments increases with each publication, revealing a complex process that remains far from being completely understood.In the past few years, literature has consistently implicated the role of microRNAs (miRNAs) in PAH. Briefly, miRNAs are s...

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Section: Molecular Contribution Of Pasmcs To Pah Phenotypesupporting

confidence: 85%

Vascular Remodeling Process in Pulmonary Arterial Hypertension, with Focus on miR‐204 and miR‐126 (2013 Grover Conference Series)

et al. 2014

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“…To test the effect of miR-204 in vivo, mice were treated with vitamin D 3 to induce calcification and simultaneously with a miR-204 agomir (miRNA mimic). In these mice, Runx2 was not upregulated and aortic calcification was similar to controls (16). Similarly, miRNA-30b and miRNA-30c (which target and downregulate Runx2) were shown to be downregulated by bone morphoge- netic protein-2 (BMP-2), and the loss or knockdown of these miRNAs in vivo increased Runx2 expression and calcification (6).…”

Section: Emerging Concepts In Vascular Calcificationmentioning

confidence: 78%

A current understanding of vascular calcification in CKD

Paloian

Giachelli

2014

American Journal of Physiology-Renal Physiology

268

264

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Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have significant cardiovascular morbidity and mortality that is in part due to the development of vascular calcification. Vascular calcification is an active, highly regulated process that shares many similarities with normal bone formation. New discoveries related to extracellular vesicles, microRNAs, and calciprotein particles continue to reveal the mechanisms that are involved in the initiation and progression of vascular calcification in CKD. Further innovations in these fields are critical for the development of biomarkers and therapeutic options for patients with CKD and ESRD.

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“…However, we now have the means to study calcification in AVS using human tissues [14,15,29], which according to our results, may be the only effective way to study the disease. Our study is limited, however, in that it only explores ALP-dependent calcification and does not address other molecular contributors including Runx2 [30], Wnts [4], UII [15], BMPs [31], and TGF-β [32]. Furthermore, we cultured our cells in OSM for 7 days for HAVICs and 12 days for BAVICs, while other studies assess calcification onset after much longer incubation times [33].…”

Section: Discussionmentioning

confidence: 99%

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Khan¹,

B²,

Al‐Kindi³

et al. 2017

Cardiovasc Pharm Open Access

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IntroductionAortic valve stenosis (AVS) is a complex disease, characterized by the thickening of the aortic valve with significant fibrosis and/or calcification [1]. Short-term symptoms include shortness of breath and fainting, while more long-term symptoms include heart failure and inevitably, death [2]. Treatment for AVS remains non-existent, with surgical intervention being the only viable option for at-risk patients. Thus, there has been interest in finding innovative approaches to treating this perilous disease [3,4].The pathogenesis of AVS is an active process involving multiple cell types and complexed underlying mechanisms [5,6]. Upon differentiation of mesenchymal-like cells to chondrogenic cells, matrix vesicles are released, containing enzymes and other factors that lead to the onset of calcification [7]. One of these enzymes, alkaline phosphatase (ALP), is a metalloenzyme that has been shown to play a profound role in calcification onset by concentrating calcium [8], mineralizing hydroxyapatite crystals [8], and inactivating inhibitory polyphosphates [9]. In humans, there are four ALP isozymes: alkaline phosphatase, tissue-nonspecific isozyme (TNALP), intestinal-type alkaline phosphatase, placental-type alkaline phosphatase, and placental-like alkaline phosphatase [10]. Two isoforms of TNALP exist: bone-specific TNALP and liver-specific TNALP, both of which are abundantly found in the serum [10]. Within the context of vascular calcification, bone TNALP is highly expressed in calcifying vascular smooth muscle cells and is likely to be responsible for calcium deposition and AVS pathogenesis [10].A multitude of studies draw conclusions regarding the pathogenesis of AVS in humans by utilizing aortic valve interstitial cells from bovine [11][12][13]. The ultimate goal of these studies is to identify mechanisms that will help us better understand calcification onset in humans. However, there is a need to directly compare these animal models to humans and assess whether or not it is plausible to make such a AbstractAortic valve stenosis (AVS) is one of the most common heart valve diseases, and surgical intervention remains the only viable treatment option. Thus, there is a need for novel and innovative treatments. One approach is to study the biological pathogenesis of this disease in hopes of finding new targets for drug therapy. Although this may be a viable option, it faces some methodological concerns. Many studies attempted to address the underlying mechanisms of this disease using aortic valves from bovine models. Although these may be viable models in certain diseased conditions, this may not be the case when studying calcification in AVS. Thus, the aim of our study was to assess the significance of drawing conclusions from bovine models to humans in the context of AVS, and investigate the role of alkaline phosphatase (ALP), an enzyme that increases calcium mineralization and deposition in aortic valve calcification. We also wanted to identify any differences in calcification when using different os...

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MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo

Abstract: Our study has shown that down-regulation of miR-204 may contribute to β-glycerophosphate-induced VSMC calcification through regulating Runx2. miR-204 represents an important new regulator of VSMC calcification and a potential therapeutic target in medial artery calcification.

Cited by 145 publications

References 39 publications

Vascular Remodeling Process in Pulmonary Arterial Hypertension, with Focus on miR‐204 and miR‐126 (2013 Grover Conference Series)

Vascular Remodeling Process in Pulmonary Arterial Hypertension, with Focus on miR‐204 and miR‐126 (2013 Grover Conference Series)

A current understanding of vascular calcification in CKD

Assessing Calcification Onset in Aortic Valve Interstitial Cells

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