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.

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

“…59 Increased [Ca 2+ ] i is required for PASMC growth 60,61 and migration 55 and has been documented in cells from hypoxic animals. 42 VGCCs contribute to stimulated proliferation 62 63 ). In particular, Ca 2+ activates nuclear factor of activated T cells (NFAT), which reduces K + channel expression, 64 providing a link between alterations in [Ca 2+ ] i , dysregulated K + channel expression/activity, and PASMC growth.…”

Potassium channels in pulmonary arterial hypertension

“…Increases in K V current preceding PASMC apoptosis induced by staurosporine were suppressed by overexpression of Bcl-2, indicating that K V channel activation-mediated apoptotic volume decrease is an early prerequisite for apoptosis [8]. In addition, the consequences of high intracellular calcium levels on PASMC growth are well documented enforcing a cellular phenotype that is resistant to apoptosis and promoting cell proliferation [9]. Based on the physiological roles and properties of K + channels in PASMCs, the implication of K + channels in PAH has been the subject of intensive research.…”

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

“…Pulmonary hypertension related to chronic obstructive pulmonary disease (COPD) is one of the most common forms of HPH and is significantly associated with increased mortality (8, 36). Currently, there is no specific therapy for pulmonary hypertension associated with COPD, which provides motivation for researchers to understand the pathogenic mechanisms of HPH.Sustained pulmonary vasoconstriction and vascular remodeling are the predominant features of HPH, both of which are respectively mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation (27). A rise of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] cyt ) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation.…”