TY - JOUR
T1 - Aryl hydrocarbon receptor and cysteine redox dynamics underlie (Mal)adaptive mechanisms to chronic intermittent hypoxia in kidney cortex
AU - Correia, Maria João
AU - Pimpão, António B.
AU - Lopes-Coelho, Filipa
AU - Sequeira, Catarina O.
AU - Coelho, Nuno R.
AU - Gonçalves-Dias, Clara
AU - Barouki, Robert
AU - Coumoul, Xavier
AU - Serpa, Jacinta
AU - Morello, Judit
AU - Monteiro, Emília C.
AU - Pereira, Sofia A.
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.
AB - We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.
KW - Animal models
KW - Arterial hypertension
KW - CYP1A1
KW - Cystine
KW - Endothelial dysfunction
KW - Non-radical oxidative species
KW - Obstructive sleep apnea
KW - Precision medicine
KW - Thiols
KW - XCT
UR - http://www.scopus.com/inward/record.url?scp=85115106295&partnerID=8YFLogxK
U2 - 10.3390/antiox10091484
DO - 10.3390/antiox10091484
M3 - Article
AN - SCOPUS:85115106295
SN - 2076-3921
VL - 10
JO - Antioxidants
JF - Antioxidants
IS - 9
M1 - 1484
ER -