Phosphodiesterase 4B activation exacerbates pulmonary hypertension induced by intermittent hypoxia by regulating mitochondrial injury and cAMP/PKA/p-CREB/PGC-1α signaling - 13/01/23
Abstract |
Proliferation of smooth muscle cells, oxidative stress, and pulmonary vasoconstriction resulting from intermittent hypoxia (IH) facilitate pulmonary hypertension (PH) in patients with obstructive sleep apnea. The role of Phosphodiesterase 4 B (PDE4B) in PH has not yet been established. Herein, we investigated whether PDE4B inhibition ameliorates experimental PH by modulating cAMP signaling. We performed an integrative analysis of PDE4B expression in Gene Expression Omnibus datasets, experimental IH-induced rat PH samples, and IH-induced pulmonary arterial smooth muscle cells (PASMCs). PDE4B expression was modulated using siRNA in vitro and a specific adeno-associated virus serotype 1 in vivo. In the databases of mouse models of IH-induced and sustained hypoxia-induced PH and in a rat model of six weeks of IH, the expression of PDE4B was up-regulated. Inhibition of PDE4B attenuated IH-induced pulmonary vascular remodeling and right ventricular hypertrophy. Our results also showed that PDE4B deficiency inhibited IH-induced proliferation of PASMCs with less mitochondrial reactive oxygen species and mitochondrial damage. Meanwhile, IH induced an increase in ATF4, which positively regulated the expression of PDE4B through transcription, and inhibition of ATF4 exerted effects similar to those of PDE4B inhibition. Mechanistically, downregulating the expression of PDE4B resulted in the activation of the cAMP/PKA/p-CREB/PGC-1α pathway in PASMCs after IH. Taken together, our present study provides evidence that inhibition of PDE4B attenuates IH-induced PH by regulating cAMP signaling.
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The mechanism of ATF4-PDE4B-cAMP signaling pathway in modulating IH-induced pulmonary hypertension. Intermittent hypoxia induced an increase in ATF4, which positively regulated the expression of PDE4B through transcription, decreasing cAMP concentration and blocking the cAMP/PKA/p-CREB/PGC-1 pathway. These alterations ultimately lead to PASMCs mitochondrial dysfunction, cell proliferation, apoptosis resistance and pulmonary artery remodeling. Therefore, targeting ATF4 or downstream PDE4B-cAMP signaling may be an effective preventive and therapeutic strategy in IH-induced pulmonary hypertension.
The mechanism of ATF4-PDE4B-cAMP signaling pathway in modulating IH-induced pulmonary hypertension. Intermittent hypoxia induced an increase in ATF4, which positively regulated the expression of PDE4B through transcription, decreasing cAMP concentration and blocking the cAMP/PKA/p-CREB/PGC-1 pathway. These alterations ultimately lead to PASMCs mitochondrial dysfunction, cell proliferation, apoptosis resistance and pulmonary artery remodeling. Therefore, targeting ATF4 or downstream PDE4B-cAMP signaling may be an effective preventive and therapeutic strategy in IH-induced pulmonary hypertension.ga1Le texte complet de cet article est disponible en PDF.
Abbreviations : PDE4B, cAMP, IH, PH, OSA, PASMCs, mtROS, PKA, AAV1, GEO, FiO2, RVSP, ChIP, siRNA
Keywords : Chronic intermittent hypoxia, Pulmonary hypertension, PDE4B, cAMP, ATF4
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Vol 158
Article 114095- février 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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