P38 mapk inhibition improves heart function in pressure-loaded right ventricular hypertrophy

Baktybek Kojonazarov, Tatyana Novoyatleva, Mario Boehm, Chris Happe, Zaneta Sibinska, Xia Tian, Amna Sajjad, Himal Luitel, Philipp Kriechling, Guido Posern, Steven M. Evans, Friedrich Grimminger, Hossein A. Ghofrani, Norbert Weissmann, Harm J. Bogaard, Werner Seeger, Ralph T. Schermuly

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-b-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-b-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-b-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.

Original languageEnglish
Pages (from-to)603-614
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume57
Issue number5
DOIs
Publication statusPublished - 1 Nov 2017

Cite this

Kojonazarov, Baktybek ; Novoyatleva, Tatyana ; Boehm, Mario ; Happe, Chris ; Sibinska, Zaneta ; Tian, Xia ; Sajjad, Amna ; Luitel, Himal ; Kriechling, Philipp ; Posern, Guido ; Evans, Steven M. ; Grimminger, Friedrich ; Ghofrani, Hossein A. ; Weissmann, Norbert ; Bogaard, Harm J. ; Seeger, Werner ; Schermuly, Ralph T. / P38 mapk inhibition improves heart function in pressure-loaded right ventricular hypertrophy. In: American Journal of Respiratory Cell and Molecular Biology. 2017 ; Vol. 57, No. 5. pp. 603-614.
@article{fc599764abcf42608b8aa24d85fb3ebb,
title = "P38 mapk inhibition improves heart function in pressure-loaded right ventricular hypertrophy",
abstract = "Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-b-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-b-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-b-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.",
keywords = "MRTF-A, P38 MAPK, Pulmonary hypertension, Right ventricle, SMADs",
author = "Baktybek Kojonazarov and Tatyana Novoyatleva and Mario Boehm and Chris Happe and Zaneta Sibinska and Xia Tian and Amna Sajjad and Himal Luitel and Philipp Kriechling and Guido Posern and Evans, {Steven M.} and Friedrich Grimminger and Ghofrani, {Hossein A.} and Norbert Weissmann and Bogaard, {Harm J.} and Werner Seeger and Schermuly, {Ralph T.}",
year = "2017",
month = "11",
day = "1",
doi = "10.1165/rcmb.2016-0374OC",
language = "English",
volume = "57",
pages = "603--614",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

}

Kojonazarov, B, Novoyatleva, T, Boehm, M, Happe, C, Sibinska, Z, Tian, X, Sajjad, A, Luitel, H, Kriechling, P, Posern, G, Evans, SM, Grimminger, F, Ghofrani, HA, Weissmann, N, Bogaard, HJ, Seeger, W & Schermuly, RT 2017, 'P38 mapk inhibition improves heart function in pressure-loaded right ventricular hypertrophy' American Journal of Respiratory Cell and Molecular Biology, vol. 57, no. 5, pp. 603-614. https://doi.org/10.1165/rcmb.2016-0374OC

P38 mapk inhibition improves heart function in pressure-loaded right ventricular hypertrophy. / Kojonazarov, Baktybek; Novoyatleva, Tatyana; Boehm, Mario; Happe, Chris; Sibinska, Zaneta; Tian, Xia; Sajjad, Amna; Luitel, Himal; Kriechling, Philipp; Posern, Guido; Evans, Steven M.; Grimminger, Friedrich; Ghofrani, Hossein A.; Weissmann, Norbert; Bogaard, Harm J.; Seeger, Werner; Schermuly, Ralph T.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 57, No. 5, 01.11.2017, p. 603-614.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - P38 mapk inhibition improves heart function in pressure-loaded right ventricular hypertrophy

AU - Kojonazarov, Baktybek

AU - Novoyatleva, Tatyana

AU - Boehm, Mario

AU - Happe, Chris

AU - Sibinska, Zaneta

AU - Tian, Xia

AU - Sajjad, Amna

AU - Luitel, Himal

AU - Kriechling, Philipp

AU - Posern, Guido

AU - Evans, Steven M.

AU - Grimminger, Friedrich

AU - Ghofrani, Hossein A.

AU - Weissmann, Norbert

AU - Bogaard, Harm J.

AU - Seeger, Werner

AU - Schermuly, Ralph T.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-b-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-b-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-b-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.

AB - Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-b-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-b-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-b-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.

KW - MRTF-A

KW - P38 MAPK

KW - Pulmonary hypertension

KW - Right ventricle

KW - SMADs

UR - http://www.scopus.com/inward/record.url?scp=85032749779&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2016-0374OC

DO - 10.1165/rcmb.2016-0374OC

M3 - Article

VL - 57

SP - 603

EP - 614

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 5

ER -