title: New mechanisms of pulmonary arterial hypertension: role of Ca²⁺ signaling.
abstract: Pulmonary arterial hypertension (PAH) is a severe and progressive disease that usually culminates in right heart failure and death if left untreated. Although there have been substantial improvements in our understanding and significant advances in the management of this disease, there is a grim prognosis for patients in the advanced stages of PAH. A major cause of PAH is increased pulmonary vascular resistance, which results from sustained vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular stiffness. In addition to other signal transduction pathways, Ca(2+) signaling in pulmonary artery smooth muscle cells (PASMCs) plays a central role in the development and progression of PAH because of its involvement in both vasoconstriction, through its pivotal effect of PASMC contraction, and vascular remodeling, through its stimulatory effect on PASMC proliferation. Altered expression, function, and regulation of ion channels and transporters in PASMCs contribute to an increased cytosolic Ca(2+) concentration and enhanced Ca(2+) signaling in patients with PAH. This review will focus on the potential pathogenic role of Ca(2+) mobilization, regulation, and signaling in the development and progression of PAH.
authors.affiliation: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Frank K
authors.initials: FK
authors.lastname: Kuhr
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Smith
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Song
authors.forename: Irena
authors.initials: I
authors.lastname: Levitan
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D021941:Caveolae / Q000502:physiology; D022461:Caveolins / Q000096:biosynthesis; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D050051:Transient Receptor Potential Channels / Q000096:biosynthesis; D014661:Vasoconstriction
chemical_list: D015220:Calcium Channels; D002352:Carrier Proteins; D022461:Caveolins; D018398:Homeodomain Proteins; D015221:Potassium Channels; C479529:RBX1 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; C491534:TLX2 protein, human; D050051:Transient Receptor Potential Channels; D002118:Calcium