DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy

Autor: Tianjing Hu, Andrew M. Kidger, Robert H. Lane, Robert A. McKnight, Kimberly M. Demos-Davies, Emma L. Robinson, Stephen M. Keyse, Marcello Rubino, Sara A. Wennersten, Mary C.M. Weiser-Evans, Bradley S Ferguson, Maria A. Cavasin, Timothy A. McKinsey, Matthew S. Stratton, Eva Nozik
Rok vydání: 2021
Předmět:
MAPK/ERK pathway
medicine.medical_specialty
Physiology
MAP Kinase Signaling System
kinase
Heart Ventricles
Hypertension
Pulmonary
Phosphatase
Myocytes
Smooth Muscle
030204 cardiovascular system & hematology
Pulmonary Artery
Vascular Remodeling
Muscle
Smooth
Vascular
03 medical and health sciences
Mice
0302 clinical medicine
Smooth muscle
Right ventricular hypertrophy
Physiology (medical)
Internal medicine
Renin–angiotensin system
pulmonary hypertension
medicine
Animals
Humans
Vasoconstrictor Agents
Cells
Cultured
smooth muscle cell
Cell Proliferation
Mice
Knockout
Hypertrophy
Right Ventricular
Rapid Report
Kinase
Cell growth
business.industry
Angiotensin II
angiotensin
medicine.disease
Pulmonary hypertension
ERK
Endocrinology
030228 respiratory system
Case-Control Studies
Dual-Specificity Phosphatases
Cardiology and Cardiovascular Medicine
business
Zdroj: American Journal of Physiology-Heart and Circulatory Physiology
ISSN: 1522-1539
Popis: Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling. NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.
Databáze: OpenAIRE
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