LncPTSR Triggers Vascular Remodeling in Pulmonary Hypertension by Regulating [Ca2+]i in Pulmonary Arterial Smooth Muscle Cells.

Abstract

Pulmonary hypertension (PH) is characterized by vascular remodeling and sustained increase in right ventricular systolic pressure. The molecular mechanisms behind PH development remain unclear. Here, a long noncoding RNA (lncRNA) attenuated by platelet-derived growth factor BB (PDGF-BB) was identified, and its functional roles were investigated in vitro and in vivo. Using RNA-sequencing data and rapid amplification of cDNA ends, an lncRNA neighboring the locus of ATPase plasma membrane Ca2+ transporting 4 (PMCA4) was identified and named lncPTSR. It is a highly conserved nuclear lncRNA and was downregulated in pulmonary arterial smooth muscle cells (PASMCs) with PDGF-BB stimulation or hypoxia induction. Gene interruption or overexpression assays revealed that lncPTSR negatively regulates rat PASMC proliferation, apoptosis, and migration. LncPTSR interruption in Sprague Dawley rats using adeno-associated virus type 9-mediated shRNA resulted in a significant increase in right ventricular systolic pressure and vascular remodeling in normoxic condition. LncPTSR knockdown also suppressed PMCA4 expression and attenuated the intracellular Ca2 + efflux of PASMCs in vitro and in vivo. Further studies suggest a complex crosstalk between lncPTSR and mitogen-activated protein kinase pathway: inhibition of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase abolishes the PDGF-BB-mediated lncPTSR downregulation, and lncPTSR plays a feedback regulation for mitogen-activated protein kinase-signaling molecules. The present study suggests that lncPTSR participates in pulmonary artery remodeling via modulating the expression of PMCA4 and intracellular Ca2 +  homeostasis downstream of PDGF-BB-driven mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling. These results suggest that lncPTSR may be a promising therapeutic target in PH treatment.

• Authors: Liyu Deng, Jidong Chen, Bin Chen, Ting Wang, Lei Yang, Jing Liao, Junbo Yi, Yuqin Chen, Jian Wang, John Linneman, Yanqin Niu, Deming Gou
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 66 Issue 5 Pg. 524-538 (05 2022) ISSN: 1535-4989 [Electronic] United States
• PMID: 35148256 (Publication Type: Journal Article)

Chemical References

• RNA, Long Noncoding
• Becaplermin
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases
• Calcium

Topics

• Animals
• Becaplermin (metabolism, pharmacology)
• Calcium (metabolism)
• Cell Proliferation
• Cells, Cultured
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hypertension, Pulmonary (genetics, metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Muscle, Smooth, Vascular (metabolism)
• Myocytes, Smooth Muscle (metabolism)
• Pulmonary Artery (metabolism)
• RNA, Long Noncoding (genetics)
• Rats
• Rats, Sprague-Dawley
• Vascular Remodeling