Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH.

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ID: 123: ROLE OF MICRORNA-1 IN REGULATING PULMONARY VASCULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.120 ◽

2016 ◽

Vol 64 (4) ◽

pp. 969.1-969 ◽

Cited By ~ 1

Author(s):

JR Sysol ◽

J Chen ◽

S Singla ◽

V Natarajan ◽

RF Machado ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Luciferase Reporter ◽

Pulmonary Vascular Remodeling ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

RationalePulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by increased pulmonary arterial pressure and resistance due in part to uncontrolled vascular remodeling. The mechanisms contributing to vascular remodeling in PAH are poorly understood and involve rampant pulmonary artery smooth muscle cell (PASMC) proliferation. We recently demonstrated the important role of sphingosine kinase 1 (SphK1), a lipid kinase producing pro-proliferative sphingosine-1-phosphate (S1P), in the development of pulmonary vascular remodeling in PAH. However, the regulatory processes involved in upregulation of SphK1 in this disease are unknown.ObjectiveIn this study, we aimed to identify novel molecular mechanisms governing the regulation of SphK1 expression, with a focus on microRNA (miR). Using both in vitro studies in pulmonary artery smooth muscle cells (PASMCs) and an in vivo mouse model of experimental hypoxia-mediated pulmonary hypertension (HPH), we explored the role of miR in controlling SphK1 expression in the development of pulmonary vascular remodeling.Methods and ResultsIn silico analysis identified hsa-miR-1-3p (miR-1) as a candidate targeting SphK1. We demonstrate miR-1 is down-regulated by hypoxia in human PASMCs and in lung tissues of mice with HPH, coinciding with upregulation of SphK1 expression. PASMCs isolated from patients with PAH had significantly reduced expression of miR-1. Transfection of human PASMCs with miR-1 mimics significantly attenuated activity of a SphK1-3'-UTR luciferase reporter construct and SphK1 protein expression. miR-1 overexpression in human PASMCs also inhibited proliferation and migration under normoxic and hypoxic conditions, both important in pathogenic vascular remodeling in PAH. Finally, we demonstrated that intravenous administration of miR-1 mimics prevents the development of experimental HPH in mice and attenuates induction of SphK1 in PASMCs.ConclusionThese data demonstrate that miR-1 expression in reduced in PASMCs from PAH patients, is modulated by hypoxia, and regulates the expression of SphK1. Key phenotypic aspects of vascular remodeling are influenced by miR-1 and its overexpression can prevent the development of HPH in mice. These studies further our understanding of the mechanisms underlying pathogenic pulmonary vascular remodeling in PAH and could lead to novel therapeutic targets.Supported by grants NIH/NHLBI R01 HL127342 and R01 HL111656 to RFM, NIH/NHLBI P01 HL98050 and R01 HL127342 to VN, American Heart Association Predoctoral Fellowship (15PRE2190004) to JRS, and NIH/NLHBI NRSA F30 Fellowship (FHL128034A) to JRS.

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Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00321.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. H853-H866 ◽

Cited By ~ 2

Author(s):

Yin Kang ◽

Guangyan Zhang ◽

Emma C. Huang ◽

Jiapeng Huang ◽

Jun Cai ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Lung Injury ◽

Arterial Hypertension ◽

Right Ventricular ◽

Vascular Remodeling ◽

Systolic Function ◽

Systolic Dysfunction ◽

Pulmonary Vascular Remodeling ◽

Pulmonary Arterial

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies. NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.

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Pathogenic Role of Store-Operated and Receptor-Operated Ca2+ Channels in Pulmonary Arterial Hypertension

Journal of Signal Transduction ◽

10.1155/2012/951497 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 13

Author(s):

Ruby A. Fernandez ◽

Premanand Sundivakkam ◽

Kimberly A. Smith ◽

Amy S. Zeifman ◽

Abigail R. Drennan ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

The Body ◽

Pathogenic Role ◽

Pulmonary Vascular Remodeling ◽

Pulmonary Vasoconstriction ◽

Voltage Dependent ◽

Pulmonary Arterial

Pulmonary circulation is an important circulatory system in which the body brings in oxygen. Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that predominantly affects women. Sustained pulmonary vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular stiffness are the major causes for the elevated pulmonary vascular resistance (PVR) in patients with PAH. The elevated PVR causes an increase in afterload in the right ventricle, leading to right ventricular hypertrophy, right heart failure, and eventually death. Understanding the pathogenic mechanisms of PAH is important for developing more effective therapeutic approach for the disease. An increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC migration and proliferation which lead to pulmonary vascular wall thickening and remodeling. It is thus pertinent to define the pathogenic role of Ca2+ signaling in pulmonary vasoconstriction and PASMC proliferation to develop new therapies for PAH. [Ca2+]cyt in PASMC is increased by Ca2+ influx through Ca2+ channels in the plasma membrane and by Ca2+ release or mobilization from the intracellular stores, such as sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER). There are two Ca2+ entry pathways, voltage-dependent Ca2+ influx through voltage-dependent Ca2+ channels (VDCC) and voltage-independent Ca2+ influx through store-operated Ca2+ channels (SOC) and receptor-operated Ca2+ channels (ROC). This paper will focus on the potential role of VDCC, SOC, and ROC in the development and progression of sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in PAH.

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New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00944.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. H1546-H1562 ◽

Cited By ~ 110

Author(s):

Frank K. Kuhr ◽

Kimberly A. Smith ◽

Michael Y. Song ◽

Irena Levitan ◽

Jason X-J. Yuan

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Right Heart Failure ◽

Altered Expression ◽

Pulmonary Vascular Remodeling ◽

Advanced Stages ◽

Pulmonary Arterial

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, Ca2+ 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 Ca2+ concentration and enhanced Ca2+ signaling in patients with PAH. This review will focus on the potential pathogenic role of Ca2+ mobilization, regulation, and signaling in the development and progression of PAH.

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Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00058.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. L723-L737 ◽

Cited By ~ 14

Author(s):

Sarah E. Hogan ◽

Maria Pia Rodriguez Salazar ◽

John Cheadle ◽

Rachel Glenn ◽

Carolina Medrano ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Mitochondrial Function ◽

Therapeutic Potential ◽

Tca Cycle ◽

Target Cells ◽

The Tca Cycle ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O2 consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.

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Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

International Journal of Molecular Sciences ◽

10.3390/ijms19103162 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3162 ◽

Cited By ~ 27

Author(s):

Mélanie Lambert ◽

Véronique Capuano ◽

Andrea Olschewski ◽

Jessica Sabourin ◽

Chandran Nagaraj ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Ion Channels ◽

Pulmonary Arterial Hypertension ◽

Therapeutic Potential ◽

Severe Disease ◽

Pulmonary Vasculature ◽

Pulmonary Vessel ◽

Vessel Remodeling ◽

Pulmonary Arterial ◽

Arterial Tone

Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na+ and Cl−). This review focuses on ion channels in the pulmonary vasculature and discusses their pathophysiological contribution to PAH as well as their therapeutic potential in PAH.

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Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00758.2013 ◽

2014 ◽

Vol 307 (3) ◽

pp. H273-H283 ◽

Cited By ~ 41

Author(s):

Aiping Liu ◽

David Schreier ◽

Lian Tian ◽

Jens C. Eickhoff ◽

Zhijie Wang ◽

...

Keyword(s):

Cardiac Output ◽

Pulmonary Arterial Hypertension ◽

Ejection Fraction ◽

Arterial Hypertension ◽

Right Ventricular ◽

Therapeutic Potential ◽

Systolic Function ◽

Arterial Compliance ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction and failure. Paradoxically, women are more frequently diagnosed with PAH but have better RV systolic function and survival rates than men. The mechanisms by which sex differences alter PAH outcomes remain unknown. Here, we sought to study the role of estrogen in RV functional remodeling in response to PAH. The SU5416-hypoxia (SuHx) mouse model of PAH was used. To study the role of estrogen, female mice were ovariectomized and then treated with estrogen or placebo. SuHx significantly increased RV afterload and resulted in RV hypertrophy. Estrogen treatment attenuated the increase in RV afterload compared with the untreated group (effective arterial elastance: 2.3 ± 0.1 mmHg/μl vs. 3.2 ± 0.3 mmHg/μl), and this was linked to preserved pulmonary arterial compliance (compliance: 0.013 ± 0.001 mm2/mmHg vs. 0.010 ± 0.001 mm2/mmHg; P < 0.05) and decreased distal muscularization. Despite lower RV afterload in the estrogen-treated SuHx group, RV contractility increased to a similar level as the placebo-treated SuHx group, suggesting an inotropic effect of estrogen on RV myocardium. Consequently, when compared with the placebo-treated SuHx group, estrogen improved RV ejection fraction and cardiac output (ejection fraction: 57 ± 2% vs. 44 ± 2% and cardiac output: 9.7 ± 0.4 ml/min vs. 7.6 ± 0.6 ml/min; P < 0.05). Our study demonstrates for the first time that estrogen protects RV function in the SuHx model of PAH in mice directly by stimulating RV contractility and indirectly by protecting against pulmonary vascular remodeling. These results underscore the therapeutic potential of estrogen in PAH.

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Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x.15.1.12 ◽

2016 ◽

Vol 15 (1) ◽

pp. 12-13

Author(s):

Adaani E. Frost ◽

Harrison W. Farber

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Lung Transplantation ◽

Small Cell ◽

Small Cell Lung ◽

Donor Organ ◽

The Road ◽

Lung Allocation Score ◽

Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

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