Contribution of TRPC channels in human and experimental pulmonary arterial hypertension

Am J Physiol Lung Cell Mol Physiol. 2023 Jun 27. doi: 10.1152/ajplung.00011.2023. Online ahead of print.ABSTRACTPulmonary arterial hypertension (PAH) is due to progressive distal pulmonary artery (PA) obstruction leading to right ventricular hypertrophy and failure. Exacerbated store-operated Ca2+ entry (SOCE) contributes to PAH pathogenesis, mediating human PA smooth muscle cells (hPASMCs) abnormalities. The transient receptor potential canonical channels (TRPC family) are Ca2+-permeable channels contributing to SOCE in different cell types, including PASMCs. However, the properties, signaling pathways, and contribution to Ca2+ signaling of each TRPC isoform are unclear in human PAH. We studied in vitro the impact of TRPC knockdown on control and PAH-hPASMCs function. In vivo, we analyzed the consequences of pharmacological TRPC inhibition using the experimental model of pulmonary hypertension (PH) induced by monocrotaline (MCT)-exposure. Compared to control-hPASMCs cells, in PAH-hPASMCs, we found a decreased TRPC4 expression, overexpression of TRPC3 and TRPC6, and unchanged TRPC1 expression. Using the siRNA strategy, we found that the knockdown of TRPC1-C3-C4-C6 reduced the SOCE and the proliferation rate of PAH-hPASMCs. Only TRPC1 knockdown decreased the migration capacity of PAH-hPASMCs. After PAH-hPASMCs exposure to the apoptosis inducer staurosporine, TRPC1-C3-C4-C6 knockdown increased the percentage of apoptotic cells, suggesting that these channels promote apoptosis r...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Source Type: research