Endothelial Dec1-PPARγ Axis Impairs Proliferation and Apoptosis Homeostasis Under Hypoxia in Pulmonary Arterial Hypertension

Abstract

Background: The hypoxia-induced pro-proliferative and anti-apoptotic characteristics of pulmonary arterial endothelial cells (PAECs) play critical roles in pulmonary vascular remodeling and contribute to hypoxic pulmonary arterial hypertension (PAH) pathogenesis. However, the mechanism underlying this hypoxic disease has not been fully elucidated.Methods: Bioinformatics was adopted to screen out the key hypoxia-related genes in PAH. Gain- and loss-function assays were then performed to test the identified hypoxic pathways in vitro. Human PAECs were cultured under hypoxic (3% O2) or normoxic (21% O2) conditions. Hypoxia-induced changes in apoptosis and proliferation were determined by flow cytometry and Ki-67 immunofluorescence staining, respectively. Survival of the hypoxic cells was estimated by cell counting kit-8 assay. Expression alterations of the target hypoxia-related genes, cell cycle regulators, and apoptosis factors were investigated by Western blot.Results: According to the Gene Expression Omnibus dataset (GSE84538), differentiated embryo chondrocyte expressed gene 1-peroxisome proliferative-activated receptor-γ (Dec1-PPARγ) axis was defined as a key hypoxia-related signaling in PAH. A negative correlation was observed between Dec1 and PPARγ expression in patients with hypoxic PAH. In vitro observations revealed an increased proliferation and a decreased apoptosis in PAECs under hypoxia. Furthermore, hypoxic PAECs exhibited remarkable upregulation of Dec1 and downregulation of PPARγ. Dec1 was confirmed to be crucial for the imbalance of proliferation and apoptosis in hypoxic PAECs. Furthermore, the pro-surviving effect of hypoxic Dec1 was mediated through PPARγ inhibition.Conclusion: For the first time, Dec1-PPARγ axis was identified as a key determinant hypoxia-modifying signaling that is necessary for the imbalance between proliferation and apoptosis of PAECs. These novel endothelial signal transduction events may offer new diagnostic and therapeutic options for patients with hypoxic PAH.

High serum Bhlhe40 levels are associated with subclinical atherosclerosis in patients with type 2 diabetes mellitus: A cross-sectional study

“…10 In vitro observation showed an elevated proliferation and a declined apoptosis of pulmonary arterial endothelial cells under hypoxia conditions by the upregulation of Bhlhe40. 12 Conversely, our previous studies found a low expression in high glucose-treated VSMCs. 5 The reasons for this discrepancy might be due to the differences in cell types, handling of samples, and study design.…”

PANoptosis: Novel insight into regulated cell death and its potential role in cardiovascular diseases (Review)

“…The differentiated embryo chondrocyte expressed gene 1-peroxisome proliferative-activated receptor-γ axis has also been delineated as a critical element in hypoxia-modulated signaling, integral to the imbalance between proliferation and apoptosis in PAECs. This finding underscores the complexity of the cellular milieu in PH and the nuanced equilibrium required for vascular homeostasis (46).…”

Circadian clock disruptions link oxidative stress and systemic inflammation to metabolic syndrome in obstructive sleep apnea patients

“…First, among all the OSA-disrupted clock genes, Dec1 shows the most prominent change and the most specific OSA effect in OSA patients during the morning ( Gaspar et al, 2021 ). Second, as a hypoxia-responsive and stress-associated protein, others and we have been found that Dec1 transcriptionally suppresses another transcriptional factor peroxisome proliferative activated receptor-γ (PPARγ), a key mediator in regulating insulin sensitivity ( Yun et al, 2002 ; Li et al, 2021 ). Third, interactions of both Dec1/PPARγ and Dec1/IL-6 occur under inflammatory or oxidative burden and involved in cellular energy metabolism ( Yun et al, 2002 ; Ning et al, 2017 ; Noshiro et al, 2020 ; Luan et al, 2021 ).…”