TY - JOUR
T1 - DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy
AU - Ferguson, Bradley S.
AU - Wennersten, Sara A.
AU - Demos-Davies, Kimberly M.
AU - Rubino, Marcello
AU - Robinson, Emma L.
AU - Cavasin, Maria A.
AU - Stratton, Matthew S.
AU - Kidger, Andrew M.
AU - Hu, Tianjing
AU - Keyse, Stephen M.
AU - McKnight, Robert A.
AU - Lane, Robert H.
AU - Nozik, Eva S.
AU - Weiser-Evans, Mary C. M.
AU - McKinsey, Timothy A.
N1 - Funding Information:
This work was supported by grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Heart and Stroke Foundation of Canada (to J. A. Simpson and K. R. Brunt) and by an Alexander Graham Bell Canada Graduate Scholarship-Doctoral (CGS D) NSERC (to L. M. Ogilvie).
Funding Information:
Present addresses: B. S. Ferguson, Dept. of Nutrition, Univ. of Nevada, Reno, NV 89557; M. S. Stratton, Dept. of Physiology and Cell Biology, The Ohio State Univ. College of Medicine, Columbus, OH 43210. Work in the Keyse laboratory was supported by Cancer Research UK Programme Grant C8227/A12053, MRC Research Grant MR/N020790/1, and a Dundee Cancer Centre Studentship (to A.M.K.). T. A. McKinsey was supported by the National Institutes of Health (NIH) Grants HL116848, HL147558, DK119594, HL127240, and HL150225 and American Heart Association (AHA) Grant 16SFRN31400013. M. Rubino and E. L. Robinson were supported by the AHA Grants 20POST35210627 and 829504, respectively. Echocardiography was supported by NIH Grant 1S10OD018156-01, entitled ?Small Animal Ultrasound Imager-Vevo 2100.? PHBI cells were funded by NIH Grant RO3 HL110783 (to E.S.N.).
Publisher Copyright:
© 2021 the American Physiological Society.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - Angiotensin
KW - ERK
KW - Kinase
KW - Pulmonary hypertension
KW - Smooth muscle cell
UR - http://www.scopus.com/inward/record.url?scp=85112189957&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00115.2021
DO - 10.1152/ajpheart.00115.2021
M3 - Article
C2 - 34142888
SN - 0363-6135
VL - 321
SP - H382–H389
JO - American Journal of Physiology - Heart and Circulatory Physiology (AJP - Heart and Circulatory Physiology)
JF - American Journal of Physiology - Heart and Circulatory Physiology (AJP - Heart and Circulatory Physiology)
IS - 2
ER -