Control of Arterial Hypertension by the AhR Blocker CH-223191: A Chronopharmacological Study in Chronic Intermittent Hypoxia Conditions.

Chronic intermittent hypoxia (CIH) is a major contributor to the development of hypertension (HTN) in obstructive sleep apnea (OSA). OSA subjects frequently display a non-dipping pattern of blood pressure (BP) and resistant HTN. After discovering that AHR-CYP1A1 axis is a druggable target in CIH-HTN, we hypothesized that CH-223191 could control BP in both active and inactive periods of the animals, recovering the BP dipping profile in CIH conditions.We evaluated the chronopharmacology of the antihypertensive efficacy of the AhR blocker CH-223191 in CIH conditions (21% to 5% of O2, 5.6 cycles/h, 10.5 h/day, in inactive period of Wistar rats). BP was measured by radiotelemetry, at 8 am (active phase) and at 6 pm (inactive phase) of the animals. The circadian variation of AhR activation in the kidney in normoxia was also assessed, measuring the CYP1A1 (hallmark of AhR activation) protein levels.Despite drug administration before starting the inactive period of the animals, CH-223191 was not able to decrease BP during the inactive phase, in CIH conditions, therefore not reverting the non-dipping profile. These results suggest that a higher dose or different time of administration of CH-223191 might be needed for an antihypertensive effect throughout the 24-h cycle.

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine.

In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.

Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex.

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.

AHR canonical pathway: in vivo findings to support novel antihypertensive strategies.

Essential hypertension (HTN) is a disease where genetic and environmental factors interact to produce a high prevalent set of almost indistinguishable phenotypes. The weak definition of what is under the umbrella of HTN is a consequence of the lack of knowledge on the players involved in environment-gene interaction and their impact on blood pressure (BP) and mechanisms. The disclosure of these mechanisms that sense and (mal)adapt to toxic-environmental stimuli might at least determine some phenotypes of essential HTN and will have important therapeutic implications. In the present manuscript, we looked closer to the environmental sensor aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor involved in cardiovascular physiology, but better known by its involvement in biotransformation of xenobiotics through its canonical pathway. This review aims to disclose the contribution of the AHR-canonical pathway to HTN. For better mirror the complexity of the mechanisms involved in BP regulation, we privileged evidence from in vivo studies. Here we ascertained the level of available evidence and a comprehensive characterization of the AHR-related phenotype of HTN. We reviewed clinical and rodent studies on AHR-HTN genetic association and on AHR ligands and their impact on BP. We concluded that AHR is a druggable mechanistic linker of environmental exposure to HTN. We conclude that is worth to investigate the canonical pathway of AHR and the expression/polymorphisms of its related genes and/or other biomarkers (e.g. tryptophan-related ligands), in order to identify patients that may benefit from an AHR-centered antihypertensive treatment.