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bioRxiv · 10.1101/2023.04.11.536344

Activation of peroxisome proliferator-activated receptor-gamma prevents monocrotaline-induced pulmonary arterial hypertension by suppressing of nuclear factor-kappa B mediated autophagy

Zhang, P.·Shi, C.·Song, J.·Dong, T.·Zhang, K.
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Abstract

To investigate the molecular mechanisms underlying autophagy inducing pulmonary vascular remodeling and rosiglitazone inhibiting pulmonary arterial hypertension (PAH). Monocrotaline (MCT) was intraperitoneally injection to induce the rat PAH model. The right ventricular hypertrophy index (RVHI), right ventricle systolic pressure (RVSP), percentage of medial wall thickness (%MT) and histomorphologic analyses were performed to evaluate the development of PAH. The translocation of nuclear factor-kappa B (NF-{kappa}B) p65 subunit from cytosol to nucleus, the protein expression levels of LC3B, Beclin 1 and RND3 were determined by western blot. Furthermore, NF-{kappa}B inhibitor, pyrrolidine dithiocarbamate (PDTC) and peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) activator, rosiglitazone, were used to inhibit the activation of NF-{kappa}B and activate PPAR{gamma} signaling, respectively. MCT injection dramatically induced PAH models in rats as manifested by the increased RVSP, RVHI, and %MT. In addition, the activation of NF-{kappa}B and autophagy were significantly enhanced and the RND3 were markedly decreased in MCT-induced PAH in rat. However, these effects could be significantly suppressed either by the supplementation of PDTC or rosiglitazone. NF-{kappa}B promotes the development of PAH by activation of autophagy and consequent down-regulation of RND3 expression. Activation of PPAR{gamma} suppresses autophagy by inhibiting NF-{kappa}B in MCT-induced PAH. Our results not only uncovered the mechanisms of PPAR{gamma} activator in the protection of PAH but also provided potential therapeutic target for PAH treatment.

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Zhang, P., Shi, C., Song, J., Dong, T., Zhang, K.. 2023-04-11. Activation of peroxisome proliferator-activated receptor-gamma prevents monocrotaline-induced pulmonary arterial hypertension by suppressing of nuclear factor-kappa B mediated autophagy. https://doi.org/10.1101/2023.04.11.536344

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