Vitamin D deficiency downregulates TASK-1 channels and induces pulmonary vascular dysfunction.

Abstract

Vitamin D (VitD) receptor regulates the expression of several genes involved in signaling pathways affected in pulmonary hypertension (PH). VitD deficiency is highly prevalent in PH, and low levels are associated with poor prognosis. We investigated if VitD deficiency may predispose to or exacerbate PH. Male Wistar rats were fed with a standard or a VitD-free diet for 5 wk. Next, rats were further divided into controls or PH, which was induced by a single dose of Su-5416 (20 mg/kg) and exposure to hypoxia (10% O2) for 2 wk. VitD deficiency had no effect on pulmonary pressure in normoxic rats, indicating that, by itself, it does not trigger PH. However, it induced several moderate but significant changes characteristic of PH in the pulmonary arteries, such as increased muscularization, endothelial dysfunction, increased survivin, and reduced bone morphogenetic protein (Bmp) 4, Bmp6, DNA damage-inducible transcript 4, and K+ two-pore domain channel subfamily K member 3 (Kcnk3) expression. Myocytes isolated from pulmonary arteries from VitD-deficient rats had a reduced whole voltage-dependent potassium current density and acid-sensitive (TASK-like) potassium currents. In rats with PH induced by Su-5416 plus hypoxia, VitD-free diet induced a modest increase in pulmonary pressure, worsened endothelial function, increased the hyperreactivity to serotonin, arterial muscularization, decreased total and TASK-1 potassium currents, and further depolarized the pulmonary artery smooth muscle cell membrane. In human pulmonary artery smooth muscle cells from controls and patients with PH, the active form of VitD calcitriol significantly increased KCNK3 mRNA expression. Altogether, these data strongly suggest that the deficit in VitD induces pulmonary vascular dysfunction.

• Authors: Maria Callejo, Gema Mondejar-Parreño, Daniel Morales-Cano, Bianca Barreira, Sergio Esquivel-Ruiz, Miguel Angel Olivencia, Grégoire Manaud, Frédéric Perros, Juan Duarte, Laura Moreno, Angel Cogolludo, Francisco Perez-Vizcaíno
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 319 Issue 4 Pg. L627-L640 (10 01 2020) ISSN: 1522-1504 [Electronic] United States
• PMID: 32726132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Potassium Channels, Tandem Pore Domain
• Vitamin D
• potassium channel subfamily K member 3

Topics

• Animals
• Humans
• Hypertension, Pulmonary (metabolism)
• Lung (metabolism, physiopathology)
• Male
• Membrane Potentials (physiology)
• Muscle, Smooth, Vascular (metabolism, physiopathology)
• Myocytes, Smooth Muscle (metabolism)
• Nerve Tissue Proteins (metabolism)
• Potassium Channels, Tandem Pore Domain (metabolism)
• Rats, Wistar
• Vitamin D (metabolism)
• Vitamin D Deficiency (metabolism)