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Emerging therapeutics in pulmonary hypertension.

ABSTRACT: Pulmonary hypertension (PH) is a progressive and often fatal illness presenting with nonspecific symptoms of dyspnea, lower extremity edema, and exercise intolerance. Pathologically, endothelial dysfunction leads to abnormal intimal and smooth muscle proliferation along with reduced apoptosis, resulting in increased pulmonary vascular resistance and elevated pulmonary pressures. PH is subdivided into five World Health Organization groups based on the disease pathology and specific cause. While there are Food and Drug Administration-approved medications for the treatment of pulmonary arterial hypertension (PAH; Group 1 PH), as well as for chronic thromboembolic PH (Group 4 PH), the morbidity and mortality remain high. Moreover, there are no approved therapies for other forms of PH (Groups 2, 3, and 5) at present. New research has identified molecular targets that mediate vasodilation, anti-inflammatory, and antifibrotic changes within the pulmonary vasculature. Given that PAH is the most commonly studied form of PH worldwide and because recent studies have led to better mechanistic understanding of this devastating disease, in this review we attempt to provide an updated overview of new therapeutic approaches under investigation for the treatment of PH, with a particular focus on PAH, as well as to offer guidelines for future investigations.

SUBMITTER: Hensley MK

PROVIDER: S-EPMC6008125 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Emerging therapeutics in pulmonary hypertension.

Hensley Matthew K MK Levine Andrea A Gladwin Mark T MT Lai Yen-Chun YC

American journal of physiology. Lung cellular and molecular physiology 20180201 5

Pulmonary hypertension (PH) is a progressive and often fatal illness presenting with nonspecific symptoms of dyspnea, lower extremity edema, and exercise intolerance. Pathologically, endothelial dysfunction leads to abnormal intimal and smooth muscle proliferation along with reduced apoptosis, resulting in increased pulmonary vascular resistance and elevated pulmonary pressures. PH is subdivided into five World Health Organization groups based on the disease pathology and specific cause. While t ...[more]

PMID: 29388467

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Project description:The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.

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Emerging therapeutics in pulmonary hypertension.

Publications

Emerging therapeutics in pulmonary hypertension.

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