A new study has identified 2 intracellular chloride channel proteins, CLIC1 and CLIC4, that play a key role in the endothelial reprogramming underlying the pathogenesis of pulmonary arterial hypertension (PAH).
The study, published in the American Journal of Respiratory Cell and Molecular Biology, found the proteins to be highly expressed in cancer and PAH.
“Pathological overexpression of CLIC proteins induces mitochondrial fragmentation, inhibits mitochondrial cristae formation and induces metabolic shift towards glycolysis in human pulmonary artery endothelial cells, consistent with changes observed in patient-derived cells,” the authors wrote. “Here we report the effects of pathological overexpression of CLIC proteins on mitochondrial structure and function in pulmonary endothelium.”
The research team cultured purchased human pulmonary artery endothelial cells (HPAECs) and endothelial late outgrowth colony forming cells (ECFCs) obtained from blood samples of 12 patients with PAH and 14 healthy volunteers as controls. Animal experiments were also conducted on a mouse model of PAH.
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The results showed that overexpression of the CLIC1 and CLIC4 proteins in human pulmonary artery endothelial cells led to mitochondrial fragmentation and altered mitochondrial dynamics in a manner consistent with changes observed in PAH endothelium. The ECFCs from patients with PAH were highly proliferative and proangiogenic, and CLIC1 and CLIC4 mRNA were found to be significantly increased in the ECFCs.
CLIC1 and CLIC4 silencing restored healthy mitochondrial dynamics in the ECFCs from patients with PAH. Mitochondrial homeostasis was also restored in the PAH mice after inhibition of CLIC1 or CLIC4.
The authors propose that changes in CLIC1 and CLIC4 expression accompany the molecular dysfunction found in PAH. They speculate that these proteins regulate the mitochondrial function, cell proliferation, and endothelial transition that occurs in the pathogenesis of PAH and therefore might be suitable therapeutic targets in this disease.
Alzaydi MM, Abdul-Salam VB, Whitwell H, et al. Intracellular chloride channels regulate endothelial metabolic reprogramming in pulmonary arterial hypertension. Am J Resp Cell Mol Biol. Published online October 20, 2022. doi:10.1165/rcmb.2022-0111OC