Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension.

An increase in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. Previously, we demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca(2+) influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here, we report that CaSR functionally interacts with TRPC6 to regulate [Ca(2+)]cyt in PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca(2+)-induced [Ca(2+)]cyt increase in IPAH-PASMC (in which CaSR is upregulated), whereas overexpression of CaSR or TRPC6 enhanced Ca(2+)-induced [Ca(2+)]cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, whereas blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice (casr(-/-)) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.

Facile Ligand Exchange of Ionic Ligand-Capped Amphiphilic Ag2S Nanocrystals for High Conductive Thin Films.

A surface ligand modification of colloidal nanocrystals (NCs) is one of the crucial issues for their practical applications because of the highly insulating nature of native long-chain ligands. Herein, we present straightforward methods for phase transfer and ligand exchange of amphiphilic Ag2S NCs and the fabrication of highly conductive films. S-terminated Ag2S (S-Ag2S) NCs are capped with ionic octylammonium (OctAH+) ligands to compensate for surface anionic charge, S2-, of the NC core. An injection of polar solvent, formamide (FA), into S-Ag2S NCs dispersed in toluene leads to an additional envelopment of the charged S-Ag2S NC core by FA due to electrostatic stabilization, which allows its amphiphilic nature and results in a rapid and effective phase transfer without any ligand addition. Because the solvation by FA involves a dissociation equilibrium of the ionic OctAH+ ligands, controlling a concentration of OctAH+ enables this phase transfer to show reversibility. This underlying chemistry allows S-Ag2S NCs in FA to exhibit a complete ligand exchange to Na+ ligands. The S-Ag2S NCs with Na+ ligands show a close interparticle distance and compatibility for uniformly deposited thin films by a simple spin-coating method. In photoelectrochemical measurements with stacked Ag2S NCs on ITO electrodes, a 3-fold enhanced current response was observed for the ligand passivation of Na+ compared to OctAH+, indicating a significantly enhanced charge transport in the Ag2S NC film by a drastically reduced interparticle distance due to the Na+ ligands.