Cryptolepine and its analogues exerted anti-TGF-β effects, promoted BMP signalling, inhibited excessive cell proliferation, and induced apoptosis in PASMCs harbouring a pathogenic BMPR2 mutation.
Does cryptolepine modulate BMP and TGF-β signaling and affect cell proliferation and apoptosis in PASMCs with BMPR2 mutations?
Cryptolepine and its analogues modulate BMP and TGF-β pathways, inhibiting proliferation and inducing apoptosis in PAH cell models, suggesting potential as novel therapeutic interventions.
Abstract Background and Aims Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder caused by narrowing of small pulmonary arteries in the lungs. Vascular remodelling observed in PAH patients are due to excessive proliferation and apoptosis resistance of the pulmonary arterial smooth muscle (PASMCs) and pulmonary arterial endothelial cells (PAECs). We have previously reported that heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2) gene underlie the majority of the familial and heritable forms of the disease and agents inhibiting hyperactive transforming growth factor beta (TGF-β) or promoting impaired bone morphogenetic protein (BMP) signalling elicit beneficial effects in cell-based and PAH animal models. Here, we report the modulation of TGF-β and BMP pathways by cryptolepine, an indoloquinoline antimalarial product. Methods The BMP and TGF-β signalling modulating effects of cryptolepine and its analogues were examined through various interdisplinary approaches including reporter assays, gene expression studies and western blot analyses. To determine the anti-proliferative and pro-apoptotic effects of the compounds, MTS and Caspase-Glo®3/7 assays were employed respectively. Finally, comet assay was performed to examine any DNA damaging effects of cryptolepines. Results The cryptolepines exert anti-TGF-β effects and promote BMP signalling through the inhibition of phosphorylation of SMAD3 proteins and augmentation of the phosphorylation of SMAD1/5 proteins, respectively. Furthermore, these compounds inhibit excessive cell proliferation, induce apoptosis in PASMCs harbouring a pathogenic BMPR2 mutation (p.R899X), and protect human lymphocytes from oxidative damage. Conclusion This is the first report demonstrating the modulation of both BMP and TGF-β pathways using quinoline compounds, which demand further preclinical investigations to aid in identifying potential novel therapeutic interventions for PAH as well as other disorders with dysregulated BMP and TGF-β signalling.
Sharmin et al. (Mon,) conducted a other in Pulmonary Arterial Hypertension (PAH). Cryptolepine and halogenated analogues was evaluated on Modulation of BMP and TGF-β pathways, cell proliferation, and apoptosis. Cryptolepine and its analogues exerted anti-TGF-β effects, promoted BMP signalling, inhibited excessive cell proliferation, and induced apoptosis in PASMCs harbouring a pathogenic BMPR2 mutation.
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