Transmembrane protein 16A/anoctamin 1 inhibitor T16A_inh‐A01 reversed monocrotaline‐induced rat pulmonary arterial hypertension

Role of Sensory Nerves in Pulmonary Fibrosis

“…While little is known about lymphatic contractile activity in the lung, in other tissue beds, increases in intracellular Ca 2+ are important in driving lymphatic pacemaker activity and contraction, and these processes are reliant on inositol triphosphate (IP3) receptors and the Ca 2+ -activated Cl − channel TMEM16A [ 190 , 191 ]. TMEM16A is overexpressed in pulmonary arterial smooth muscle cells in patients with idiopathic PH and contributes to vasoconstrictor and vascular remodeling responses [ 192 ], with similar effects observed in rodent models of PH [ 193 , 194 ]. Lung lymphatic collecting vessels from mice have minimal smooth muscle cells to drive lymph propulsion, suggesting the forward fluid flow is primarily driven by changes in pressure that occur during respiration [ 183 ].…”

Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension

“…In PH pathophysiology: In the PAH mouse model, TMEM16A expression in pulmonary arteries has been shown to co-localize with a specific VSMC marker that mediates PASMCs proliferation and pulmonary arteriole remodeling [121,122]. Studies in patients with iPAH confirm that TMEM16A is up-regulated, promoting increase in Cl − currents in the PASMCs and inducing proliferation of PASMCs.…”

“…However, it did not lead to full recovery. Thus, T16Ainh-A01 appears to be a promising drug in improving vascular remodeling [121]. Increase in TMEM16A expression in healthy PAECs has functional consequences in PAECs, such as changes in Ca 2+ dynamics and eNOS activity, decreasing NO production, promoting PAECs proliferation, wound healing, tube formation and relaxation of pulmonary artery mediated by ACh [125].…”