RT Journal Article
SR Electronic
T1 Loss of Amphiregulin drives inflammation and endothelial apoptosis in pulmonary hypertension
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101264
DO 10.26508/lsa.202101264
VO 5
IS 11
A1 Jonathan Florentin
A1 Jingsi Zhao
A1 Yi-Yin Tai
A1 Wei Sun
A1 Lee L Ohayon
A1 Scott P O’Neil
A1 Anagha Arunkumar
A1 Xinyi Zhang
A1 Jianhui Zhu
A1 Yassmin Al Aaraj
A1 Annie Watson
A1 John Sembrat
A1 Mauricio Rojas
A1 Stephen Y Chan
A1 Partha Dutta
YR 2022
UL https://www.life-science-alliance.org/content/5/11/e202101264.abstract
AB Pulmonary hypertension (PH) is a vascular disease characterized by elevated pulmonary arterial pressure, leading to right ventricular failure and death. Pathogenic features of PH include endothelial apoptosis and vascular inflammation, which drive vascular remodeling and increased pulmonary arterial pressure. Re-analysis of the whole transcriptome sequencing comparing human pulmonary arterial endothelial cells (PAECs) isolated from PH and control patients identified AREG, which encodes Amphiregulin, as a key endothelial survival factor. PAECs from PH patients and mice exhibited down-regulation of AREG and its receptor epidermal growth factor receptor (EGFR). Moreover, the deficiency of AREG and EGFR in ECs in vivo and in vitro heightened inflammatory leukocyte recruitment, cytokine production, and endothelial apoptosis, as well as diminished angiogenesis. Correspondingly, hypoxic mice lacking Egfr in ECs (cdh5cre/+ Egfrfl/fl) displayed elevated RVSP and pulmonary remodeling. Computational analysis identified NCOA6, PHB2, and RRP1B as putative genes regulating AREG in endothelial cells. The master transcription factor of hypoxia HIF-1⍺ binds to the promoter regions of these genes and up-regulates their expression in hypoxia. Silencing of these genes in cultured PAECs decreased inflammation and apoptosis, and increased angiogenesis in hypoxic conditions. Our pathway analysis and gene silencing experiments revealed that BCL2-associated agonist of cell death (BAD) is a downstream mediator of AREG. BAD silencing in ECs lacking AREG mitigated inflammation and apoptosis, and suppressed tube formation. In conclusion, loss of Amphiregulin and its receptor EGFR in PH is a crucial step in the pathogenesis of PH, promoting pulmonary endothelial cell death, influx of inflammatory myeloid cells, and vascular remodeling.