NAADP-induced intracellular calcium ion is mediated by the TPCs (two-pore channels) in hypoxia-induced pulmonary arterial hypertension.

Abstract

Pulmonary arterial hypertension (PAH) is a form of obstructive vascular disease. Chronic hypoxic exposure leads to excessive proliferation of pulmonary arterial smooth muscle cells and pulmonary arterial endothelial cells. This condition can potentially be aggravated by [Ca2+ ] i mobilization. In the present study, hypoxia exposure of rat's model was established. Two-pore segment channels (TPCs) silencing was achieved in rats' models by injecting Lsh-TPC1 or Lsh-TPC2. The effects of TPC1/2 silencing on PAH were evaluated by H&E staining detecting pulmonary artery wall thickness and ELISA assay kit detecting NAADP concentrations in lung tissues. TPC1/2 silencing was achieved in PASMCs and PAECs, and cell proliferation was detected by MTT and BrdU incorporation assays. As the results shown, NAADP-activated [Ca2+ ]i shows to be mediated via two-pore segment channels (TPCs) in PASMCs, with TPC1 being the dominant subtype. NAADP generation and TPC1/2 mRNA and protein levels were elevated in the hypoxia-induced rat PAH model; NAADP was positively correlated with TPC1 and TPC2 expression, respectively. In vivo, Lsh-TPC1 or Lsh-TPC2 infection significantly improved the mean pulmonary artery pressure and PAH morphology. In vitro, TPC1 silencing inhibited NAADP-AM-induced PASMC proliferation and [Ca2+ ]i in PASMCs, whereas TPC2 silencing had minor effects during this process; TPC2 silencing attenuated NAADP-AM- induced [Ca2+ ]i and ECM in endothelial cells, whereas TPC1 silencing barely ensued any physiological changes. In conclusion, TPC1/2 might provide a unifying mechanism within pulmonary arterial hypertension, which can potentially be regarded as a therapeutic target.

• Authors: Wen Hu, Fei Zhao, Ling Chen, Jiamin Ni, Yongliang Jiang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 15 Pg. 7485-7499 (08 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 34263977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Calcium Channels
• Tpcn1 protein, rat
• Tpcn2 protein, rat
• NADP
• NAADP
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels (genetics, metabolism)
• Cells, Cultured
• Endothelial Cells (metabolism)
• Endothelium, Vascular (cytology, metabolism)
• Hypertension, Pulmonary (etiology, metabolism)
• Hypoxia (complications, metabolism)
• Male
• Muscle, Smooth, Vascular (cytology, metabolism)
• Myocytes, Smooth Muscle (metabolism)
• NADP (analogs & derivatives, metabolism)
• Rats
• Rats, Wistar