scholarly journals G protein‐coupled receptor expression and function in pulmonary artery smooth muscle cells: new targets in pulmonary arterial hypertension (1090.3)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Daniel McDonald ◽  
Nakon Aroonsakool ◽  
Ohmin Kwon ◽  
Paul Insel ◽  
Fiona Murray
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
G Protein ◽  
Receptor Expression ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
And Function ◽  
G Protein Coupled

scholarly journals Ca2+-Activated Cl- Currents of Pulmonary Artery Smooth Muscle Cells are Enhanced in Monocrotaline-Induced Pulmonary Arterial Hypertension in the Rat

2010 ◽  
Vol 98 (3) ◽  
pp. 123a
Author(s):  
Abigail S. Forrest ◽  
Marissa L. Huebner ◽  
Yasamin Omoomian ◽  
Ramon J. Ayon ◽  
Normand Leblanc ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

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

2016 ◽  
Vol 64 (4) ◽  
pp. 969.1-969 ◽  
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.

Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

2007 ◽  
Vol 292 (6) ◽  
pp. C2297-C2305 ◽  
Author(s):  
Shen Zhang ◽  
Hui Dong ◽  
Lewis J. Rubin ◽  
Jason X.-J. Yuan
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Smooth Muscle Cells ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Reverse Mode ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a trigger for pulmonary vasoconstriction and a stimulus for PASMC proliferation and migration. Multiple mechanisms are involved in regulating [Ca2+]cyt in human PASMC. The resting [Ca2+]cyt and Ca2+ entry are both increased in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH), which is believed to be a critical mechanism for sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in these patients. Here we report that protein expression of NCX1, an NCX family member of Na+/Ca2+ exchanger proteins is upregulated in PASMC from IPAH patients compared with PASMC from normal subjects and patients with other cardiopulmonary diseases. The Na+/Ca2+ exchanger operates in a forward (Ca2+ exit) and reverse (Ca2+ entry) mode. By activating the reverse mode of Na+/Ca2+ exchange, removal of extracellular Na+ caused a rapid increase in [Ca2+]cyt, which was significantly enhanced in IPAH PASMC compared with normal PASMC. Furthermore, passive depletion of intracellular Ca2+ stores using cyclopiazonic acid (10 μM) not only caused a rise in [Ca2+]cyt due to Ca2+ influx through store-operated Ca2+ channels but also mediated a rise in [Ca2+]cyt via the reverse mode of Na+/Ca2+ exchange. The upregulated NCX1 in IPAH PASMC led to an enhanced Ca2+ entry via the reverse mode of Na+/Ca2+ exchange, but did not accelerate Ca2+ extrusion via the forward mode of Na+/Ca2+ exchange. These observations indicate that the upregulated NCX1 and enhanced Ca2+ entry via the reverse mode of Na+/Ca2+ exchange are an additional mechanism responsible for the elevated [Ca2+]cyt in PASMC from IPAH patients.

Sign in / Sign up

Export Citation Format

Share Document