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Therapeutics in pulmonary hypertension
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Maria F. Acosta, Don Hayes, Jeffrey R. Fineman, Jason X.-J. Yuan, Stephen M. Black, Heidi M. Mansour
Mutations in genes that encode proteins involved in the Tumor necrosis factor β (TNF-β) signaling pathway are implicated in the development of PH. These mutations include Bone morphogenetic protein receptor type 2 (BMPR2), Activin A receptor like type 1 (ACVRL1), Endoglin (ENG), Smad8, Smad1, Smad5, and Caveolin-1. TNF-β signaling pathway controls growth, differentiation, and apoptosis of various cell types including pulmonary vascular (ECs) and SMCs (12). Thus, mutations in genes involved in the TGF-β signaling pathway may be responsible for the abnormal proliferation of pulmonary vascular SMCs and may promote ECs apoptosis (12).
Uterine fibroids and the endometrium
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Deborah E. Ikhena, Serdar E. Bulun
Submucosal fibroids secrete increased levels of TGF-β3, which leads to downregulation of bone morphogenetic protein receptor type II (BMPR-2) expression in ESF and subsequent ESF resistance to BMP2 (22). This resistance to BMP2 negatively affects cell proliferation and differentiation and subsequently impairs decidualization and implantation site formation (52). Given the essential role of BMP2 and its downstream targets in decidualization and successful implantation, endometrial resistance to BMP2 in the presence of uterine fibroids has the potential to result in suboptimal decidualization and defective implantation. This would manifest clinically as decreased implantation and higher incidences of spontaneous abortion.
Lung transplantation for pulmonary hypertension
Published in Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell, LUNG Transplantation, 2016
Stéphane Collaud, Marc de Perrot
PAH probably develops because of a combination of environmental factors and genetic predisposition to pulmonary vascular disease. Environmental factors may include additional acquired genetic mutation, viral infection (including HIV), a chronic inflammatory condition (connective tissue disease), drugs (appetite suppressants), and variations in the hemodynamics of the pulmonary circulation (congenital systemic-to-pulmonary shunts). Mutations with a role in PAH have been found in genes encoding for bone morphogenetic protein receptor type II (BMPR2), activin receptor–like kinase 1 (ALK1), 5-hydroxytryptamine transporter (5HTT), endoglin (ENG), mothers against decapentaplegic homolog 9 (SMAD9), caveolin-1 (CAV1), and potassium channel subfamily K member 3 (KCNK3).8–14 Genetic predisposition and exposure to environmental factors probably lead to dysregulation of the microenvironment of the lung, which in turn results in an imbalance between agents with promitotic or vasoconstrictive (endothelin) and antimitotic or vasodilatative (nitric oxide, prostacyclin) effects.15 Indeed, an increase in the production of endothelin, as well as a lack of nitric oxide and prostacyclin production, has been suggested in different studies.16–21 Consequently, vasoconstriction and vascular remodeling occur, which in turn leads to increased pulmonary vascular resistance (PVR) and PH.
Update on pulmonary arterial hypertension research: proceedings from a meeting of experts
Published in Current Medical Research and Opinion, 2018
Vallerie McLaughlin, Matthew Bacchetta, David Badesch, Raymond Benza, Charles Burger, Kelly Chin, Robert Frantz, Adaani Frost, Anna Hemnes, Nick H. Kim, Erika B. Rosenzweig, Lewis Rubin
Dr Anna Hemnes reviewed pre-clinical PAH data from the past year, helping to demonstrate the importance of using animal and in vitro models (including microRNAs) to explore PAH, and show that PAH affects the entire body, and that genetic studies can help elucidate PAH pathology and treatment. She first gave an overview of the latest pre-clinical data by explaining that bone morphogenetic protein receptor type 2 (BMPR2) mutations are common with heritable PAH4, and suppression of BMPR2-mediated signaling is common in idiopathic and other PAH types. Further, it is well-known that, although many more women than men have heritable PAH5, a specific role for estrogen interacting with BMPR2 is unknown. Insight from rodent microRNA studies and human pathology samples showed that one microRNA (miR-150-5p) regulates BMP signaling through its target SMURF1 (Smad ubiquitylation regulatory factor 1) and, thereby, may cause PAH pathology6. Additionally, in a BMPR2-mutation mouse model of PAH, an estrogen metabolite upregulated a different microRNA (miR-29), thereby promoting insulin resistance, leading to PAH development7. These data suggest reduced BMPR2 signaling as a mechanism by which estrogen may mediate insulin resistance and PAH development. Loss of KCNK3, encoding a potassium channel and recently identified as a genetic cause of PAH, was shown to be key for PAH pathogenesis using rodent models8. Lastly, rodent data showed that the leukemia drug, dasatanib, may cause PAH by increasing vascular changes, as well as altering endothelial cell function and increasing apoptosis9.
Is sotatercept, which traps activins and growth differentiation factors, a new dawn in treating pulmonary arterial hypertension (PAH)?
Published in Expert Opinion on Biological Therapy, 2023
Sotatercept is an activin receptor type IIA fusion protein (ActRIIA-Fc) [1]. In heritable PAH, several mutations in the genes have been demonstrated including those encoding bone morphogenetic protein receptor type 2 (BMPR2), which is a member of the transforming growth factor-β superfamily of signaling molecules [5]. Normally, in pulmonary circulation, there is a balance between proliferative and antiproliferative factors, which include BMP. In PAH, it is proposed that there is a downregulation of the BMPR2 pathway leading to a prominence of the upregulation pathway that is mediated by activins growth differentiation factors acting at the ActRIIA. As an ActRIIA-Fc, sotatercept removes these proliferative factors to correct the imbalance in PAH [2].
Emerging drugs for the treatment of idiopathic pulmonary fibrosis: 2020 phase II clinical trials
Published in Expert Opinion on Emerging Drugs, 2021
Giacomo Sgalla, Marialessia Lerede, Luca Richeldi
Pulmonary arterial hypertension (PH) can develop in IPF patients and represents a strong predictor of mortality. Its underlying pathogenetic mechanisms are not fully understood. An old paradigm suggested that the elevation of pulmonary pressure was the result of lung parenchyma fibrotic destruction with subsequent pulmonary vascular remodeling, hypoxic vasoconstriction and loss of capillary density. In the recent years, the idea of an active process characterized by dysregulation of molecular targets such as vascular endothelial growth factor (VEGF), adenosine, bone morphogenetic protein receptor type II (BMPR2), and hypoxia-inducible factor 1 alpha (HIF-1α) is gaining more credit [4].