RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension
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RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension. / Rhodes, Christopher J; Im, Hogune; Cao, Aiqin; Hennigs, Jan K; Wang, Lingli; Sa, Silin; Chen, Pin-I; Nickel, Nils P; Miyagawa, Kazuya; Hopper, Rachel K; Tojais, Nancy F; Li, Caiyun G; Gu, Mingxia; Spiekerkoetter, Edda; Xian, Zhaoying; Chen, Rui; Zhao, Mingming; Kaschwich, Mark; Del Rosario, Patricia A; Bernstein, Daniel; Zamanian, Roham T; Wu, Joseph C; Snyder, Michael P; Rabinovitch, Marlene.
In: AM J RESP CRIT CARE, Vol. 192, No. 3, 01.08.2015, p. 356-66.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension
AU - Rhodes, Christopher J
AU - Im, Hogune
AU - Cao, Aiqin
AU - Hennigs, Jan K
AU - Wang, Lingli
AU - Sa, Silin
AU - Chen, Pin-I
AU - Nickel, Nils P
AU - Miyagawa, Kazuya
AU - Hopper, Rachel K
AU - Tojais, Nancy F
AU - Li, Caiyun G
AU - Gu, Mingxia
AU - Spiekerkoetter, Edda
AU - Xian, Zhaoying
AU - Chen, Rui
AU - Zhao, Mingming
AU - Kaschwich, Mark
AU - Del Rosario, Patricia A
AU - Bernstein, Daniel
AU - Zamanian, Roham T
AU - Wu, Joseph C
AU - Snyder, Michael P
AU - Rabinovitch, Marlene
PY - 2015/8/1
Y1 - 2015/8/1
N2 - RATIONALE: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.OBJECTIVES: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.METHODS: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.MEASUREMENTS AND MAIN RESULTS: Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries.CONCLUSIONS: The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.
AB - RATIONALE: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.OBJECTIVES: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.METHODS: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.MEASUREMENTS AND MAIN RESULTS: Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries.CONCLUSIONS: The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.
KW - Adolescent
KW - Adult
KW - Animals
KW - Bone Morphogenetic Protein Receptors, Type II
KW - Cells, Cultured
KW - Endothelium, Vascular
KW - Familial Primary Pulmonary Hypertension
KW - Female
KW - Humans
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Middle Aged
KW - Sequence Analysis, RNA
KW - Signal Transduction
KW - Transcriptome
KW - Young Adult
U2 - 10.1164/rccm.201408-1528OC
DO - 10.1164/rccm.201408-1528OC
M3 - SCORING: Journal article
C2 - 26030479
VL - 192
SP - 356
EP - 366
JO - AM J RESP CRIT CARE
JF - AM J RESP CRIT CARE
SN - 1073-449X
IS - 3
ER -
