Endothelial Nox1 oxidase assembly in human pulmonary arterial hypertension; driver of Gremlin1-mediated proliferation.

Ghouleh, Imad Al; Sahoo, Sanghamitra; Meijles, Daniel N; Amaral, Jefferson H; de Jesus, Daniel S; Sembrat, John; Rojas, Mauricio; Goncharov, Dmitry A; Goncharova, Elena A; Pagano, Patrick J

Ghouleh, Imad Al; Sahoo, Sanghamitra; Meijles, Daniel N; Amaral, Jefferson H; de Jesus, Daniel S; Sembrat, John; Rojas, Mauricio; Goncharov, Dmitry A; Goncharova, Elena A; Pagano, Patrick J.

Afiliación

Ghouleh IA; Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Sahoo S; Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Meijles DN; Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Amaral JH; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
de Jesus DS; Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Sembrat J; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Rojas M; Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Goncharov DA; Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Goncharova EA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
Pagano PJ; Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.

Clin Sci (Lond) ; 131(15): 2019-2035, 2017 Aug 01.

Article en En | MEDLINE | ID: mdl-28522681

RESUMEN

Pulmonary arterial hypertension (PAH) is a rapidly degenerating and devastating disease of increased pulmonary vessel resistance leading to right heart failure. Palliative modalities remain limited despite recent endeavors to investigate the mechanisms underlying increased pulmonary vascular resistance (PVR), i.e. aberrant vascular remodeling and occlusion. However, little is known of the molecular mechanisms responsible for endothelial proliferation, a root cause of PAH-associated vascular remodeling. Lung tissue specimens from PAH and non-PAH patients and hypoxia-exposed human pulmonary artery endothelial cells (ECs) (HPAEC) were assessed for mRNA and protein expression. Reactive oxygen species (ROS) were measured using cytochrome c and Amplex Red assays. Findings demonstrate for the first time an up-regulation of NADPH oxidase 1 (Nox1) at the transcript and protein level in resistance vessels from PAH compared with non-PAH patients. This coincided with an increase in ROS production and expression of bone morphogenetic protein (BMP) antagonist Gremlin1 (Grem1). In HPAEC, hypoxia induced Nox1 subunit expression, assembly, and oxidase activity leading to elevation in sonic hedgehog (SHH) and Grem1 expression. Nox1 gene silencing abrogated this cascade. Moreover, loss of either Nox1, SHH or Grem1 attenuated hypoxia-induced EC proliferation. Together, these data support a Nox1-SHH-Grem1 signaling axis in pulmonary vascular endothelium that is likely to contribute to pathophysiological endothelial proliferation and the progression of PAH. These findings also support targeting of Nox1 as a viable therapeutic option to combat PAH.

Asunto(s)

Proliferación Celular; Hipertensión Pulmonar/enzimología; Péptidos y Proteínas de Señalización Intercelular/metabolismo; NADPH Oxidasas/metabolismo; Adulto; Anciano; Células Endoteliales/citología; Células Endoteliales/metabolismo; Femenino; Proteínas Hedgehog/genética; Proteínas Hedgehog/metabolismo; Humanos; Hipertensión Pulmonar/genética; Hipertensión Pulmonar/metabolismo; Hipertensión Pulmonar/fisiopatología; Péptidos y Proteínas de Señalización Intercelular/genética; Masculino; Persona de Mediana Edad; NADPH Oxidasa 1; NADPH Oxidasas/genética; Arteria Pulmonar/enzimología; Especies Reactivas de Oxígeno/metabolismo; Transducción de Señal

Palabras clave

NADPH oxidase; endothelial cells; gremlin1; hedgehog; pulmonary hypertension; reactive oxygen species

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: NADPH Oxidasas / Péptidos y Proteínas de Señalización Intercelular / Proliferación Celular / Hipertensión Pulmonar Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Sci (Lond) Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google