Zinc attenuates monocrotaline-induced pulmonary hypertension in rats through upregulation of A20.

Publication date: Oct 01, 2024

Pulmonary hypertension (PH) is characterized by excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), in which inflammatory signaling caused by activation of the NF-_705B pathway plays an important role. A20 is an important negative regulator of the NF-_705B pathway, and zinc promotes the expression of A20 and exerts a protective effect against various diseases (e. g. COVID19) by inhibiting the inflammatory signaling. The role of A20 and intracellular zinc signaling in PH has been explored, but the extracellular zinc signaling is not well understood, and whether zinc has protective effects on PH is still elusive. Using inductively coupled plasma mass spectrometry (ICP-MS), we studied the alteration of trace elements during the progression of monocrotaline (MCT)-induced PH and found that serum zinc concentration was decreased with the onset of PH accompanied by abnormalities of other three elements, including copper, chromium, and magnesium. Zinc chloride injection with the dosage of 5 mg/kg intraperitoneally partially corrected this abnormality and inhibited the progression of PH. Zinc supplementation induced the expression of A20 in lung tissue and reduce the inflammatory responses. In vitro, zinc supplementation time-dependently upregulated the expression of A20 in PASMCs, therefore correcting the excessive proliferation and migration of cells caused by hypoxia. Using genetically encoded-FRET based zinc probe, we found that these effects of zinc ions are not achieved by entering cells, but most likely by activating cell surface zinc receptor (ZnR/GPR39). These results provide the first evidence of the effectiveness of zinc supplementation in the treatment of PH.

Concepts Keywords
Cardiol A20
Covid19 Animals
Inflammatory Cell Movement
Magnesium Cell Proliferation
Spectrometry Extracellular zinc signaling
GPR39
Hypertension, Pulmonary
Lung
Male
Monocrotaline
Monocrotaline
Myocytes, Smooth Muscle
NF-kappa B
NF-kappa B
Pulmonary Artery
Pulmonary hypertension
Rats
Rats, Sprague-Dawley
Signal Transduction
TNFAIP3 protein, rat
Up-Regulation
Zinc
Zinc

Semantics

Type Source Name
drug DRUGBANK Zinc
disease MESH pulmonary hypertension
disease IDO role
disease MESH COVID19
drug DRUGBANK Medium-chain triglycerides
disease MESH abnormalities
drug DRUGBANK Copper
drug DRUGBANK Chromium
drug DRUGBANK Magnesium
drug DRUGBANK Zinc chloride
disease MESH hypoxia
pathway REACTOME Signal Transduction

Original Article

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