A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples

Paola Caruso, Yvonne Dempsie, Hannah C. Stevens, Robert A. McDonald, Lu Long, Ruifang Lu, Kevin White, Kirsty M. Mair, John D. McClure, Mark Southwood, Paul Upton, Mei Xin, Eva van Rooij, Eric N. Olson, Nicholas W. Morrell, Margaret R. MacLean, Andrew H. Baker

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

RATIONALE:: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. OBJECTIVE:: We assessed the role of miR-145 in PAH. METHODS AND RESULTS:: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice. CONCLUSIONS:: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.

LanguageEnglish
Pages290-300
Number of pages11
JournalCirculation Research
Volume111
Issue number3
DOIs
Publication statusPublished - 20 Jul 2012

Fingerprint

Pulmonary Hypertension
Pulmonary Artery
Lung
Smooth Muscle Myocytes
Up-Regulation
Right Ventricular Hypertrophy
Untranslated RNA
Mutation
Ventricular Pressure
MicroRNAs
Knockout Mice
Smooth Muscle
Down-Regulation
Polymerase Chain Reaction
Familial Primary Pulmonary Hypertension

Keywords

  • pulmonary hypertension
  • hypoxia
  • molecular biology
  • smooth muscle cells
  • microRNA
  • smooth muscle differentiation
  • remodeling

Cite this

Caruso, P., Dempsie, Y., Stevens, H. C., McDonald, R. A., Long, L., Lu, R., ... Baker, A. H. (2012). A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circulation Research, 111(3), 290-300. https://doi.org/10.1161/CIRCRESAHA.112.267591
Caruso, Paola ; Dempsie, Yvonne ; Stevens, Hannah C. ; McDonald, Robert A. ; Long, Lu ; Lu, Ruifang ; White, Kevin ; Mair, Kirsty M. ; McClure, John D. ; Southwood, Mark ; Upton, Paul ; Xin, Mei ; van Rooij, Eva ; Olson, Eric N. ; Morrell, Nicholas W. ; MacLean, Margaret R. ; Baker, Andrew H. / A role for miR-145 in pulmonary arterial hypertension : evidence from mouse models and patient samples. In: Circulation Research. 2012 ; Vol. 111, No. 3. pp. 290-300.
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abstract = "RATIONALE:: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. OBJECTIVE:: We assessed the role of miR-145 in PAH. METHODS AND RESULTS:: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice. CONCLUSIONS:: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.",
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author = "Paola Caruso and Yvonne Dempsie and Stevens, {Hannah C.} and McDonald, {Robert A.} and Lu Long and Ruifang Lu and Kevin White and Mair, {Kirsty M.} and McClure, {John D.} and Mark Southwood and Paul Upton and Mei Xin and {van Rooij}, Eva and Olson, {Eric N.} and Morrell, {Nicholas W.} and MacLean, {Margaret R.} and Baker, {Andrew H.}",
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Caruso, P, Dempsie, Y, Stevens, HC, McDonald, RA, Long, L, Lu, R, White, K, Mair, KM, McClure, JD, Southwood, M, Upton, P, Xin, M, van Rooij, E, Olson, EN, Morrell, NW, MacLean, MR & Baker, AH 2012, 'A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples' Circulation Research, vol. 111, no. 3, pp. 290-300. https://doi.org/10.1161/CIRCRESAHA.112.267591

A role for miR-145 in pulmonary arterial hypertension : evidence from mouse models and patient samples. / Caruso, Paola; Dempsie, Yvonne; Stevens, Hannah C.; McDonald, Robert A.; Long, Lu; Lu, Ruifang; White, Kevin; Mair, Kirsty M.; McClure, John D.; Southwood, Mark; Upton, Paul; Xin, Mei; van Rooij, Eva; Olson, Eric N.; Morrell, Nicholas W.; MacLean, Margaret R.; Baker, Andrew H.

In: Circulation Research, Vol. 111, No. 3, 20.07.2012, p. 290-300.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A role for miR-145 in pulmonary arterial hypertension

T2 - Circulation Research

AU - Caruso, Paola

AU - Dempsie, Yvonne

AU - Stevens, Hannah C.

AU - McDonald, Robert A.

AU - Long, Lu

AU - Lu, Ruifang

AU - White, Kevin

AU - Mair, Kirsty M.

AU - McClure, John D.

AU - Southwood, Mark

AU - Upton, Paul

AU - Xin, Mei

AU - van Rooij, Eva

AU - Olson, Eric N.

AU - Morrell, Nicholas W.

AU - MacLean, Margaret R.

AU - Baker, Andrew H.

PY - 2012/7/20

Y1 - 2012/7/20

N2 - RATIONALE:: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. OBJECTIVE:: We assessed the role of miR-145 in PAH. METHODS AND RESULTS:: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice. CONCLUSIONS:: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.

AB - RATIONALE:: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. OBJECTIVE:: We assessed the role of miR-145 in PAH. METHODS AND RESULTS:: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice. CONCLUSIONS:: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.

KW - pulmonary hypertension

KW - hypoxia

KW - molecular biology

KW - smooth muscle cells

KW - microRNA

KW - smooth muscle differentiation

KW - remodeling

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UR - https://www.ahajournals.org/journal/res

U2 - 10.1161/CIRCRESAHA.112.267591

DO - 10.1161/CIRCRESAHA.112.267591

M3 - Article

VL - 111

SP - 290

EP - 300

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 3

ER -