Abstract
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.
Highlights
Pulmonary arterial hypertension (PAH), which is defined in humans as a resting mean pulmonary artery pressure of 20 mmHg or above, with pulmonary vascular resistance of three woods units, is a deadly disease [1]
We demonstrate that dual-specificity phosphatase 5 (DUSP5), an inducible nuclear MKP, which is highly specific for the classical ERK1/2 mitogen-activated protein kinase (MAPK) [13], functions as a negative regulator of angiotensin II (ANG II)-mediated pulmonary artery smooth muscle cells (SMCs) (PASMC) proliferation
Together with findings employing cultured cells, these data suggest that DUSP5 functions as a negative regulator of PASMC proliferation, and that disruption of this circuit leads to adverse pulmonary vascular remodeling and pulmonary hypertension (PH)
Summary
Pulmonary arterial hypertension (PAH), which is defined in humans as a resting mean pulmonary artery pressure of 20 mmHg or above, with pulmonary vascular resistance of three woods units, is a deadly disease [1]. Pulmonary hypertension (PH) restricts blood flow through the pulmonary arterial circulation, leading to elevated pulmonary vascular resistance and often resulting in right ventricular (RV) heart failure. DUSP5 SUPPRESSES ERK SIGNALING IN SMOOTH MUSCLE CELLS component of PH, it is believed that more effective therapeutic strategies will be based on the combined use of vasodilators and drugs that target vascular cell proliferation and growth [2]. The molecular mechanisms governing pulmonary vascular remodeling need to be better defined to guide development of novel, antiproliferative therapies for PH
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