Study Finds Potential Therapeutic Target in Piezo1 Ion Channel
The levels of Piezo1, an ion channel that senses membrane tension in cells, was found to be increased in the lung blood vessels of patients with idiopathic pulmonary arterial hypertension (PAH) and in animal models of pulmonary hypertension (PH), a study says.
Research showed that these higher levels trigger certain signaling pathways in pulmonary arterial endothelial cells (PAECs) which line lung blood vessels. This may stimulate the contraction and uncontrolled growth of pulmonary artery smooth muscle cells (PASMCs), ultimately promoting the development of PAH.
Compounds that target the activity of Piezo1 in lung vessels could potentially be used to treat pulmonary hypertension, researchers say.
The study, “Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension,” was published in the American Journal of Physiology-Cell Physiology.
When blood flows through the lung arteries, it causes mechanical stretching and constant stress. In PH, this may be exacerbated because even more blood accumulates in the lung vessels, causing a prolonged mechanical stretch of the lung vessel walls.
In hypertension and inflammation, a process called osmotic stretch can cause PAECs and PASMCs to swell and produce pressure on cell membranes. Ion channels, such as Piezo1, have the ability to sense cell membrane stretch and promote the influx of calcium ions into the cell and stimulate signaling pathways.
However, information is lacking about the role of Piezo channels in lung blood vessels and whether they contribute to the progression of PAH and PH. To address this, a team of researchers from the U.S. and China based at the University of California and University of Arizona College of Medicine sought to evaluate the production and function of Piezo1 in pulmonary cells from patients with PAH and animal models of PH.
PAECs were obtained from six donors and six patients with idiopathic (meaning of unknown cause) PAH. The team also induced PH-like disease in rats and mice using several methods. To mimic severe disease, rats were given monocrotaline, which causes damage to the pulmonary arteries and hypertension, or a compound called sugen 5416 in combination with hypoxia (low oxygen). In addition, mice were exposed to low levels of oxygen for three to four weeks (chronic hypoxia-induced PH) to mimic milder disease.
Results showed that levels of Piezo1’s protein and mRNA (an intermediate molecule in protein production, derived from genes) were increased in pulmonary arterial cells from patients with idiopathic PAH, as well as in cells from rats and mouse models of PH, compared to controls.
Then, the team found that stretching of the cell membrane of human PAECs led to increased activation in signaling proteins, pERK and pAKT, related to cell proliferation and gene expression (activity). Removing calcium from the medium surrounding the cells decreased this activity. In addition, in lung cells from patients with idiopathic PAH, levels of pAKT were higher than those in normal PAECs, under osmotic stretch.
Piezo1’s role in these effects was confirmed in another set of experiments. By knocking down Piezo1 in cells with small interference RNA (small, synthesized RNA molecules), during osmotic stretch, activation of ERK and AKT was inhibited.
Notch signaling, another signaling pathway, is associated with the progression of pulmonary hypertension. Pulmonary arterial cells can function as signal-sending cells to activate Notch receptors in PASMCs. In this study, the researchers observed that molecules that bind and activate Notch were upregulated in PAECs under osmotic stretch.
To verify if blocking Piezo1 channels could be used as a therapeutic strategy, mice with PH-like disease were given GsmTx4, a spider venom peptide that inhibits tension-sensing channels like Piezo1. Peptides are small chains of amino acids, the building blocks of proteins.
The team showed that the venom could partially improve clinical parameters associated with PH. In mice, GsmTx4 significantly reduced right ventricular systolic pressure (a measure of the pressure inside the artery that supplies blood to the lungs), mean pulmonary arterial pressure, and the Fulton index — a measure of enlargement of the heart’s right ventricle.
“These data indicate that upregulated Piezo1 and enhanced [sensing of mechanical triggers] in lung vascular cells may play an important pathogenic [disease-related] role in the development of PAH and PH,” the scientists wrote.