AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension

Brock, Matthias; Samillan, Victor; Trenkmann, Michelle; Schwarzwald, Colin C.; Ulrich, Silvia; Gassmann, Max; Østergaard, Louise; Speich, Rudolf; Huber, Lars C

doi:10.1093/eurheartj/ehs060

Cited by 137 publications

(116 citation statements)

References 24 publications

(28 reference statements)

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“…Overexpression of this miRNA cluster resulted in direct transcript binding of miR-17-5p and miR-20a (24) and consequent expression of BMPR2. Correspondingly, in vivo inhibition of several members of the cluster, using oligonucleotide inhibitors (i.e., antagomiRs) or targeted genetic deletion of the entire cluster, was shown to improve experimental PH (25)(26)(27). These beneficial effects were attributed at least in part to the restoration of BMPR2 expression and the up-regulation of the cyclin-dependent kinase inhibitor p21 (25,27).…”

Section: Metabolism and Proliferationmentioning

confidence: 99%

“…Correspondingly, in vivo inhibition of several members of the cluster, using oligonucleotide inhibitors (i.e., antagomiRs) or targeted genetic deletion of the entire cluster, was shown to improve experimental PH (25)(26)(27). These beneficial effects were attributed at least in part to the restoration of BMPR2 expression and the up-regulation of the cyclin-dependent kinase inhibitor p21 (25,27). In addition to being the target of miRNAs, BMPR2 signaling also represses expression of another critical miRNA, miR-145.…”

Section: Metabolism and Proliferationmentioning

confidence: 99%

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Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

Chun

Bonnet²,

Chan

2017

Am J Respir Crit Care Med

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Section: Metabolism and Proliferationmentioning

confidence: 99%

Section: Metabolism and Proliferationmentioning

confidence: 99%

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

Chun

Bonnet²,

Chan

2017

Am J Respir Crit Care Med

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“…or treat vascular remodelling and improve haemody namics in experimental models of the disease [59][60][61][62].…”

Section: Review Articlementioning

confidence: 99%

Pulmonary hypertension: Classification and pathobiology

2014

Cardiovasc Med

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SummaryPulmonary hypertension is defined as an increase of the mean pulmonary arterial pressure above 25 mm Hg and, as such, the diagnosis requires invasive haemo dynamic measurement by right heart catheterisation. More than just a single disease, pulmonary hyperten sion is an umbrella term that includes many different disorders and pathophysiological entities. However, most forms of pulmonary hypertension share a final common pathway, in particular the trias of vasocon striction, microthrombosis and vascular remodelling. The classification of pulmonary hypertension has been subjected to many changes within the last decade. At the same time, major achievements in our understand ing of the complex pathobiology have been made. Here, these developments are discussed in the light of the re cently published report from the fifth World Sympo sium on pulmonary hypertension. Definition and haemodynamicsPulmonary arterial pressure (PAP) is a function of car diac output, left atrial pressure and pulmonary vascu lar resistance. The pulmonary circulation is a lowpres sure system and the mean pulmonary arterial pressure (mPAP) does not exceed 20 mm Hg in healthy individ uals [1]. Pulmonary hypertension is defined as an in crease of the mPAP above 25 mm Hg. Pressure values ranging from 21 to 24 mm Hg have been associated with a high risk to develop overt pulmonary hyperten sion in a subgroup of patients, for example those with connective tissue disease [2], but otherwise these pa tients are not well defined and not much data exist on the prognostic and therapeutic consequences. Use of the term "borderline pulmonary hypertension" is thus not recom mended [3]. Increasing age [4] and body weight [5] have been associ ated with a rise of systolic pulmo nary arterial pressure (sPAP) and might explain the gap between nor mal mPAP and pulmonary hyper tension.The presence of pulmonary hypertension might be determined by echocardiography, which, depending on the underlying cause of elevated pulmonary pressure, provides an excellent screening tool. However, sensitiv ity and specificity of this method is limited [6]. Diagno sis is thus confirmed by invasive haemodynamic as sessment with right heart catheterisation at rest. An inadequate elevation of pulmonary pressure upon ex ercise has been part of former definitions of pulmonary hypertension but, due to lack of standardisation, is no longer a criterion.The differentiation of pulmonary hypertension due to left heart disease from the other forms is crucial. As suggested by guidelines, the pulmonary arterial wedge pressure (PAWP, also known as "wedge pressure") is used to estimate left atrial pressure in clinical practice. In healthy subjects, PAWP reflects left atrial pressure, which is extensively determined by left ventricular enddiastolic pressure (LVEDP). Several conditions in terfere with this assumption and may lead to misclas sification of pulmonary hypertension. Since pulmonary vessels are not stiff pipes but rather compressible tubes, an increase of the alveolar pressure (e.g., ...

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“…It is suggested that more than 60% of the human genome is regulated by miRNAs 6 . In the context of PH, miRNAs have emerged as important pathogenetic factors 7,8,9 that mediate intracellular signaling events 10 and act as post-transcriptional regulators for the expression of BMPR2 11,12,13,14 .…”

Section: Introductionmentioning

confidence: 99%

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A

Brock

Haider

Vogel

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumor suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130-CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A. These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension. AbstractExcessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumour suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130 -CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A.These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension.

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AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension

Abstract: This is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling.

Cited by 137 publications

References 24 publications

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

Pulmonary hypertension: Classification and pathobiology

The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A

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