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Novel Developments on the Associatio...

Pimpao, Antonio Manuel Bacalhau,

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Novel Developments on the Association of the AHR-CYP1A1 Axis and Arterial Hypertension Related to Obstructive Sleep Apnea /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Novel Developments on the Association of the AHR-CYP1A1 Axis and Arterial Hypertension Related to Obstructive Sleep Apnea // Antonio Manuel Bacalhau Pimpao.
作者:	Pimpao, Antonio Manuel Bacalhau,
面頁冊數:	1 electronic resource (101 pages)
附註:	Source: Masters Abstracts International, Volume: 86-02.
Contained By:	Masters Abstracts International86-02.
標題:	Physiology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31165502
ISBN:	9798383782958

Novel Developments on the Association of the AHR-CYP1A1 Axis and Arterial Hypertension Related to Obstructive Sleep Apnea /
Pimpao, Antonio Manuel Bacalhau,

Novel Developments on the Association of the AHR-CYP1A1 Axis and Arterial Hypertension Related to Obstructive Sleep Apnea /Antonio Manuel Bacalhau Pimpao. - 1 electronic resource (101 pages)

Source: Masters Abstracts International, Volume: 86-02.

Chronic intermittent hypoxia (CIH) is responsible for the development of systemic hypertension (HTN) in patients with obstructive sleep apnea (OSA). OSA is a common cause of resistant HTN. CIH promotes AHR activation, particularly in the kidney, with a consequent increase in Cyp1a1expression. Moreover, using an animal model of CIHHTN, it was demonstrated that the AHR antagonist (CH-223191) might represent a promising anti-hypertensive molecule. This pharmacological effect was only apparent in animals' active period. However, available information on CH-223191 pharmacological pathways in kidney is scarce, as they are the mechanisms that associate CYP1A1 to blood pressure control.We herein focused on Cyp1a1 in kidney cortex by investigating its circadian variation as well as the gender-differences and the impact of IH chronicity in its expression (Western Blot). Transcriptomic analysis using Next-Gen RNA-Seq and bioinformatics allowed the identification of molecular mechanisms by which CH-223191 acts, both in normoxia- and CIH-exposed animals.The results indicate that the circadian pattern of CYP1A1 is opposite between male and female. For the first time is also described that the impact of IH in Cyp1a1 is dependent on the duration of IH exposure. Indeed, the effect is opposite in short- and long-term exposure: a short-term exposure (not enough to induce HTN) decreases Cyp1a1 expression and a long-term exposure, when HTN is already established, increased Cyp1a1 expression. Moreover, the pharmacological pathways of CH-223191 in kidney cortex were also disclosed. In normoxia, CH-223191 mostly under-expressed genes, but in CIH conditions it mostly over-expressed genes. Some of the identified genes are involved in BP regulation and/or in (dys)metabolic features.This work represents a forward step towards an advance regarding the relevance of the AHR-CYP1A1 axis activation in OSA-HTN, paving the way for innovative drugs for this particular type of HTN, which is difficult to control with the available anti-hypertensive drugs.

English

ISBN: 9798383782958Subjects--Topical Terms:

518431
Physiology.

Novel Developments on the Association of the AHR-CYP1A1 Axis and Arterial Hypertension Related to Obstructive Sleep Apnea /
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520 $a Chronic intermittent hypoxia (CIH) is responsible for the development of systemic hypertension (HTN) in patients with obstructive sleep apnea (OSA). OSA is a common cause of resistant HTN. CIH promotes AHR activation, particularly in the kidney, with a consequent increase in Cyp1a1expression. Moreover, using an animal model of CIHHTN, it was demonstrated that the AHR antagonist (CH-223191) might represent a promising anti-hypertensive molecule. This pharmacological effect was only apparent in animals' active period. However, available information on CH-223191 pharmacological pathways in kidney is scarce, as they are the mechanisms that associate CYP1A1 to blood pressure control.We herein focused on Cyp1a1 in kidney cortex by investigating its circadian variation as well as the gender-differences and the impact of IH chronicity in its expression (Western Blot). Transcriptomic analysis using Next-Gen RNA-Seq and bioinformatics allowed the identification of molecular mechanisms by which CH-223191 acts, both in normoxia- and CIH-exposed animals.The results indicate that the circadian pattern of CYP1A1 is opposite between male and female. For the first time is also described that the impact of IH in Cyp1a1 is dependent on the duration of IH exposure. Indeed, the effect is opposite in short- and long-term exposure: a short-term exposure (not enough to induce HTN) decreases Cyp1a1 expression and a long-term exposure, when HTN is already established, increased Cyp1a1 expression. Moreover, the pharmacological pathways of CH-223191 in kidney cortex were also disclosed. In normoxia, CH-223191 mostly under-expressed genes, but in CIH conditions it mostly over-expressed genes. Some of the identified genes are involved in BP regulation and/or in (dys)metabolic features.This work represents a forward step towards an advance regarding the relevance of the AHR-CYP1A1 axis activation in OSA-HTN, paving the way for innovative drugs for this particular type of HTN, which is difficult to control with the available anti-hypertensive drugs.
520 $a A hipoxia cronica intermitente (HCI) e responsavel pelo desenvolvimento de hipertensao sistemica em pacientes com apneia obstrutiva do sono (AOS), que e a causa mais comum de hipertensao resistente. A HCI promove a ativacao do AHR no rim, com consequente aumento de Cyp1a1. Num modelo animal de hipertensao arterial por exposicao a HCI, mostramos que um antagonista do AHR (CH-223191) pode representar uma promissora molecula anti-hipertensora. Este efeito foi apenas observado no periodo ativo dos animais. No entanto, a informacao disponivel acerca das vias farmacologicas do CH-223191 no rim e escassa, sendo estes os mecanismos que associam o CYP1A1 ao controlo da pressao arterial.Focamo-nos no Cyp1a1 no rim cortex investigando a sua variacao circadiana, assim como as diferencas entre generos e o impacto da cronicidade da hipoxia intermitente na sua expressao (Western Blot). Uma analise transcriptomica utilizando RNA-Seq e bioinformatica permitiu a identificacao dos mecanismos moleculares pelos quais o CH223191 atua, em animais expostos a normoxia e a HCI.Os resultados indicam que o padrao circadiano do CYP1A1 e oposto entre os generos. Pela primeira vez foi tambem descrito que o impacto da hipoxia intermitente no Cyp1a1 depende da duracao da exposicao. Alias, os efeitos sao opostos entre uma exposicao curta e longa: uma exposicao curta (insuficiente para induzir hipertensao arterial) diminui o Cyp1a1, mas uma exposicao prolongada (hipertensao estabelecida) aumenta a regulacao do Cyp1a1. Alem disso, as vias farmacologicas do CH-223191 no rim cortex foram reveladas. Em normoxia, o CH-223191 maioritariamente sub-expressa genes, mas a HCI maioritariamente sobre-expressa genes. Alguns dos genes identificados estao envolvidos na regulacao da pressao arterial e/ou caracteristicas metabolicas.Este trabalho contribuiu para compreender a relevancia da ativacao do AHR na hipertensao da AOS, abrindo caminho para novos farmacos inovadores para o tratamento da hipertensao resistente, dificil de controlar com os farmacos antihipertensores disponiveis.
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