Smurf1 ubiquitin ligase causes downregulation of BMP receptors and is induced in monocrotaline and hypoxia models of pulmonary arterial hypertension

Murakami, Katsuji; Mathew, Rajamma; Huang, Jing; Farahani, Reza Masteri; Peng, Hong; Olson, Susan C.; Etlinger, Joseph D.

doi:10.1258/ebm.2010.009383

Cited by 50 publications

(50 citation statements)

References 41 publications

(57 reference statements)

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“…Furthermore, the reduction in the expression of BMPRII has been reported in patients with secondary PAH, albeit less than what was observed in patients with idiopathic PAH without BMPRII mutation (5,108,123). In addition, a reduction in the expression of BMPRII has been reported in the MCT and hypoxia-induced PH (86,107). Smurf-1, which induces ubiquitination and degradation of BMPRII, is upregulated in both MCT and hypoxia models of PH, thus contributing to the reduction in BMPRII expression (86).…”

Section: Caveolae and Caveolin-1mentioning

confidence: 91%

“…In addition, a reduction in the expression of BMPRII has been reported in the MCT and hypoxia-induced PH (86,107). Smurf-1, which induces ubiquitination and degradation of BMPRII, is upregulated in both MCT and hypoxia models of PH, thus contributing to the reduction in BMPRII expression (86). Interestingly, a part of BMPRII colocalizes with caveolin-1 in caveolae (105).…”

Section: Caveolae and Caveolin-1mentioning

confidence: 98%

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Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

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Section: Caveolae and Caveolin-1mentioning

confidence: 91%

Section: Caveolae and Caveolin-1mentioning

confidence: 98%

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…The BMPRII is downregulated and BMP-Smad signaling is inhibited. This potentiates MAPK pathways and could be responsible for the observed proliferation and remodeling of the pulmonary vasculature (Murakami et al, 2010).…”

Section: Evidence From Animal Models Of Pahmentioning

confidence: 99%

Deregulation of BMP Signaling in the Pathogenesis of Pulmonary Hypertension

Boeck¹,

Dijke²

2011

Pulmonary Hypertension - From Bench Research to Clinical Challenges

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“…The most connected target within this network, and the one with the most conserved miR-140-5p binding site was Smurf1 mRNA. Smurf1 is a E3 ubiquitin ligase that targets type I BMP receptors (including BMPR2 [18]) and downstream signalling mediators [19] for ubiquitination and degradation. Through these actions Smurf1 acts a negative regulator of BMPR2 signalling.…”

Section: Editorialmentioning

confidence: 99%