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Keywords = PAH channelopathy

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25 pages, 7983 KiB  
Article
Metabolic Deregulation in Pulmonary Hypertension
by Rajamma Mathew, Sanda Iacobas, Jing Huang and Dumitru Andrei Iacobas
Curr. Issues Mol. Biol. 2023, 45(6), 4850-4874; https://doi.org/10.3390/cimb45060309 - 3 Jun 2023
Cited by 4 | Viewed by 2542
Abstract
The high morbidity and mortality rate of pulmonary arterial hypertension (PAH) is partially explained by metabolic deregulation. The present study complements our previous publication in “Genes” by identifying significant increases of the glucose transporter solute carrier family 2 (Slc2a1), beta nerve growth factor [...] Read more.
The high morbidity and mortality rate of pulmonary arterial hypertension (PAH) is partially explained by metabolic deregulation. The present study complements our previous publication in “Genes” by identifying significant increases of the glucose transporter solute carrier family 2 (Slc2a1), beta nerve growth factor (Ngf), and nuclear factor erythroid-derived 2-like 2 (Nfe2l2) in three standard PAH rat models. PAH was induced by subjecting the animals to hypoxia (HO), or by injecting with monocrotaline in either normal (CM) or hypoxic (HM) atmospheric conditions. The Western blot and double immunofluorescent experiments were complemented with novel analyses of previously published transcriptomic datasets of the animal lungs from the perspective of the Genomic Fabric Paradigm. We found substantial remodeling of the citrate cycle, pyruvate metabolism, glycolysis/gluconeogenesis, and fructose and mannose pathways. According to the transcriptomic distance, glycolysis/gluconeogenesis was the most affected functional pathway in all three PAH models. PAH decoupled the coordinated expression of many metabolic genes, and replaced phosphomannomutase 2 (Pmm2) with phosphomannomutase 1 (Pmm1) in the center of the fructose and mannose metabolism. We also found significant regulation of key genes involved in PAH channelopathies. In conclusion, our data show that metabolic dysregulation is a major PAH pathogenic factor. Full article
(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)
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21 pages, 1343 KiB  
Review
Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension
by Gabriel Redel-Traub, Kevin J. Sampson, Robert S. Kass and Michael S. Bohnen
Biomolecules 2022, 12(10), 1341; https://doi.org/10.3390/biom12101341 - 22 Sep 2022
Cited by 12 | Viewed by 4189
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in [...] Read more.
Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the KCNK3 gene that encodes the two-pore-domain potassium channel KCNK3 (or TASK-1) and loss-of-function mutations in the ABCC8 gene that encodes a key subunit, SUR1, of the ATP-sensitive potassium channel (KATP) were established as the first two potassium channelopathies in human cohorts with pulmonary arterial hypertension. Moreover, voltage-gated potassium channels (Kv) represent a third family of potassium channels with genetic changes observed in association with PAH. While other ion channel genes have since been reported in association with PAH, this review focuses on KCNK3, KATP, and Kv potassium channels as promising therapeutic targets in PAH, with recent experimental pharmacologic discoveries significantly advancing the field. Full article
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11 pages, 1117 KiB  
Review
Channelopathy Genes in Pulmonary Arterial Hypertension
by Carrie L. Welch and Wendy K. Chung
Biomolecules 2022, 12(2), 265; https://doi.org/10.3390/biom12020265 - 7 Feb 2022
Cited by 8 | Viewed by 4036
Abstract
Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in [...] Read more.
Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in ~13% of adults and 43% of children with PAH. Knowledge of genetic diagnoses can inform clinical management of PAH, including multimodal medical treatment, surgical intervention and transplantation decisions, and screening for associated conditions, as well as risk stratification for family members. Roles for rare variants in three channelopathy genes—ABCC8, ATP13A3, and KCNK3—have been validated in multiple PAH cohorts, and in aggregate explain ~2.7% of PAH cases. Complete or partial loss of function has been demonstrated for PAH-associated variants in ABCC8 and KCNK3. Channels can be excellent targets for drugs, and knowledge of mechanisms for channel mutations may provide an opportunity for the development of PAH biomarkers and novel therapeutics for patients with hereditary PAH but also potentially more broadly for all patients with PAH. Full article
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21 pages, 5123 KiB  
Article
Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells
by Hélène Le Ribeuz, Florent Dumont, Guillaume Ruellou, Mélanie Lambert, Thierry Balliau, Marceau Quatredeniers, Barbara Girerd, Sylvia Cohen-Kaminsky, Olaf Mercier, Stéphanie Yen-Nicolaÿ, Marc Humbert, David Montani, Véronique Capuano and Fabrice Antigny
Int. J. Mol. Sci. 2020, 21(19), 7400; https://doi.org/10.3390/ijms21197400 - 7 Oct 2020
Cited by 19 | Viewed by 3987
Abstract
The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. [...] Read more.
The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs. Full article
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension 2.0)
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