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The Patient with Non-Group 2 Pulmonary Hypertension
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Sophia Anastasia Mouratoglou, George Giannakoulas
Patients with sporadic or familial PAH should be advised on genetic testing and counseling because of the strong possibility that they may carry a disease-causing mutation and a BMPR2 mutation screening should be offered. When no BMPR2 mutations are identified, screening for other, rarer mutations may be considered (ACVRL1 and mutations in ENG, KCNK3, CAV1 genes, etc.). Patients with sporadic or familial pulmonary veno-occlusive disease/ pulmonary capillary hemangiomatosis (PVOD/PCH) should be tested for EIF2AK4 mutations as the presence of a bi-allelic EIF2AK4 mutation is sufficient to confirm PVOD/PCH without lung biopsy.1,2
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.
Pulmonary vascular diseases
Published in Louis-Philippe Boulet, Applied Respiratory Pathophysiology, 2017
Annie C. Lajoie, Vincent Mainguy, SéBastien Bonnet, Steeve Provencher
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in resistance to blood flow engendered by the conjugated effects of vasoconstriction, pulmonary blood vessels remodeling, and in situ thrombosis (Figure 7.7) [30]. The underlying physiopathology of the disease remains poorly understood. This group of PH includes different entities such as idiopathic pulmonary hypertension (IPAH), hereditary PAH (HPAH), PAH associated with drugs and toxins, as well as associated pulmonary arterial hypertension (APAH) including connective tissue disease, congenital heart diseases, HIV, portopulmonary hypertension, and others. A germline mutation in the gene encoding a type II receptor of the TGF-β superfamily (Bone Morphogenic Protein Receptor II or BMPR2) is identified in 75% of familial PAH and 10%–30% of “sporadic” PAH [31–34]. These mutations are rarely observed in other forms of PAH. However, BMPR2 expression is reduced even in the absence of mutations [35]. More recently, other mutations associated with HPAH were identified, including activin-like receptor kinase-1 (ALK1), endoglin (ENG), mothers against decapentaplegic 9 (Smad 9), and the potassium channel subfamily K member 3 (KCNK3) [34,36]. Nevertheless, other genes could be involved, possibly from the BMP/TGF-β pathway, which plays an important role in regulating pulmonary vasculature. Since the penetrance of the mutations remains low (10%–30%), the development of PAH probably requires a genetic predisposition coupled with certain risk factors. Nongenetic abnormalities are also involved in the progression of disease (Table 7.2) [30].
The molecular rationale for therapeutic targeting of glutamine metabolism in pulmonary hypertension
Published in Expert Opinion on Therapeutic Targets, 2019
Thomas Bertero, Dror Perk, Stephen Y. Chan
Haploinsufficient loss-of-function mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene, a member of the transforming growth factor-beta (TGF-β) superfamily, account for at least 80% of the hereditary and about 20% of the idiopathic PAH cases [115,116]. Other TGF-β/bone morphogenetic protein (BMP) signaling pathway components have also been identified as pathogenic, such as the Activin A Receptor-Like Type 1 (ACVRL1), a type I membrane glycoprotein endoglin (ENG), the secreted ligand growth differentiation factor 2 (GDF2), the SMAD family member 9 (SMAD9), and the scaffolding protein caveolin 1 (CAV1), offering convincing verification for the pivotal role dysregulated BMP signaling has in the context of PAH disease progression. More recently, alterations in genes not immediately related to TGF-β/BMP signaling, including the potassium two-pore domain channel subfamily K member 3, KCNK3 [117,118], the T-box transcription factor 4 (TBX4), the water channel aquaporin 1 (AQP1), the cation-transporting ATPase 13A3 (ATP13A3), the amino-sensing serine/threonine-protein kinase General Control Nonderepressible 2 (GCN2), and SOX17 have been linked to PAH [7,119]. Yet, the contribution of factors genetically associated with PAH to vascular cell metabolism has not been investigated in depth, and only recent evidence has emerged regarding the possible contribution of these factors to glutamine metabolism.
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.
Design of hydroxy-α-sanshool loaded nanostructured lipid carriers as a potential local anesthetic
Published in Drug Delivery, 2022
Fengming Tan, Lulu Xu, Yanling Liu, Huan Li, Dahan Zhang, Cuiying Qin, Yang Han, Jing Han
Local anesthetic is widely used to lessen pain in the oral procedure (Boyce et al., 2016) by binding to voltage gated Na+ (Nav) channels to block influx of sodium into axons (Dib-Hajj et al., 2009). In fact, local anesthetic is basically divided into amides and ester (Wang et al., 2021), such as lidocaine (Zhao et al., 2018) and benzocaine (Lamey, 2005). Sichuan pepper (Zanthoxylum piperitum), also known as ‘toothache trees’, is widely used to treat toothache and rheumatoid arthritis in native cultures such as African, Native American, and Asian. Previous studies have shown that an active alkylamide constituent extracted from Zanthoxylum piperitum is hydroxy-α-sanshool (HAS), which causes numbness (Bryant & Mezine, 1999) and analgesia (Sugai et al., 2005) during treatment of toothache. HAS not only could induce tingly numbness by targeting and inhibiting two-pore KCNK channels (KCNK3, KCNK9, and KCNK18) (Bautista et al., 2008), but also could act on distinct somatosensory neuron subtypes to mediate sensitivity to pain by blocking various Nav channels such as Nav1.7 (Tsunozaki et al., 2012, 2013). Among the Nav channels subtypes, HAS has strong inhibitory effect on Nav1.3 and Nav1.7 channels, which predominantly expressed in somatosensory neurons such as dorsal root ganglion (DRG) neurons (Black et al., 1996), Aδ mechanical nociceptors (Michael et al., 2012), etc. Besides, HAS can be absorbed rapidly after oral administration or subcutaneous injection (Iwabu et al., 2010; Munekage et al., 2011; Rong et al., 2016), suggesting that HAS might serve as a potential local anesthetic for oral surgery. However, HAS is extremely unstable against oxygen, light, and heat, which restricts its applications in local anesthetic.