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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2019.tde-31032020-115431
Document
Author
Full name
Antonio Garcia Soares Júnior
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Costa, Soraia Kátia Pereira (President)
Ferro, Emer Suavinho
Pedreira Filho, Walter dos Reis
Prada, Patrícia de Oliveira
Title in Portuguese
Efeito da exposição precoce ao poluente 1,2-naftoquinona sobre a função vascular e cardíaca: papel dos canais iônicos receptores de potencial transitório (TRP).
Keywords in Portuguese
1,2-naftoquinona
Artéria mesentérica
Artéria pulmonar
Átrio direito
Abstract in Portuguese
A poluição do ar ambiente (PAA) e do material particulado (MP2,5) estão sendo associados à efeitos adversos na saúde, embora pouco se sabe sobre os efeitos de PAA contaminantes do MP, como a 1,2-naftoquinona (1,2-NQ). Objetivou-se neste estudo avaliar o efeito in vitro e da exposição inalatória precoce da 1,2-NQ sobre a função atrial e cardiovascular (CV) de camundongos, além de investigar potenciais mecanismos, com ênfase em receptores de potencial transitório (TRP). No átrio direito (AD) isolado de camundongos, a adição in vitro da 1,2-NQ elevou a frequência atrial (FA) espontânea e reduziu o cronotropismo positivo frente a agonistas b-adrenérgico, sendo este revertido pelo bloqueio de receptores b1. Na artéria mesentérica (AM) ou pulmonar (AP) de camundongos selvagens, a 1,2-NQ causou vasocontração concentração-dependente, que foi abolida na AM do animal KO TRPA1, e exacerbada pelo bloqueio do TRPV1 (capsazepina; CPZ) e TRPV4 (HC-067047). Na AP de animais selvagens e KO para TRPV1 e TRPA1, a 1,2-NQ reduziu o relaxamento evocado por acetilcolina (ACh). Na AM, a 1,2-NQ reduziu a sensibilidade (pD2) a ACh, sendo este efeito abolido na AM de animais KO TRPA1 e inalterada em KO TRPV1. No AD de animais expostos a 1,2-NQ, a FA (pD2) frente a NE foi reduzida, sendo este efeito revertido pelo bloqueio do TRPV1, e exacerbado pelo antagonista TRPV4. No AD desses animais, a FA (Emax) frente a NE foi reduzida pelo bloqueio do TRPC5, ML-204, e observou-se um aumento na expressão (RNAm) dos receptores HCN4, TRPA1, TRPV1, b2 e b3, mas não de canais/proteínas envolvidas na homeostase do Ca2+ (ex.: RyR2, Serca2a, Cav1.2). Na AP destes, observou-se aumento P<0,05 da expressão (RNAm) para o fator Nrf2, sendo este efeito potencializado pelo bloqueio do TRPV1. Camundongos expostos a 1,2-NQ não apresentaram alterações na pressão arterial caudal, mas exibiram alterações nos parâmetros RR, SDRR, RMSSD, LF/HF do ECG, e na sensibilidade (PD2) a fenilefrina (FE) e ACh na AP isolada. O bloqueio dos TRPV1 e TRPV4 exacerbou o efeito da FE e inibiu a resposta da ACh, respectivamente, na AP de animais expostos a 1,2-NQ, e estimulou a fibrilação atrial frente a ouabaína. Em conclusão, estes resultados mostram, pela primeira vez, o potencial molecular dos receptores TRP (TRPV1) e b1 nas alterações funcionais em AD e sistema CV murino frente a adição in vitro ou exposição neonatal in vivo a 1,2-NQ, revelando a vulnerabilidade da idade aos efeitos adversos da 1,2-NQ. Estes achados funcionais e moleculares servem ainda como indicadores de susceptibilidade ao desencadeamento de disfunções CV frente a 1,2-NQ.
Title in English
Effect of early exposure to the pollutant 1,2-naphthoquinose on the vascular and cardiac functions: Role of Transient Receptor Potential ionic channels.
Keywords in English
1,2-naphthoquinone
Mesenteric artery
Pulmonary artery
Right atria
Abstract in English
Environmental air pollution (EAP) and particulate matter (PM2.5) are being associated with adverse health effects, although little is known about the effects of PM contaminant EAP, such as 1,2-naphthoquinone (1,2 -NQ). The objective of this study was to evaluate the in vitro effect and early inhalation exposure of 1,2-NQ on atrial and cardiovascular (CV) function of mice, in addition to investigating potential mechanisms, with emphasis on transient potential receptors (TRP). In the right atrium (RA) isolated from mice, in vitro 1,2-NQ addition increased the spontaneous atrial frequency (AF) and reduced the positive chronotropism to b-adrenergic agonists, which was reversed by b1 receptor blockade. In the mesenteric (MA) or pulmonary (PA) arteries of wild mice, 1,2-NQ caused concentration-dependent vasoconstriction, which was abolished in MA of KO TRPA1 animal, and exacerbated by TRPV1 (capszepine; CPZ) and TRPV4 (HC-067047). In wildtype PA and KO for TRPV1 and TRPA1, 1,2-NQ reduced acetylcholine evoked relaxation (ACh). In MA, 1,2-NQ reduced the sensitivity (pD2) to ACh, and this effect was abolished in MA of TRPA1 KO animals and unchanged in TRPV1 KO. In RA of animals exposed to 1,2- NQ, FA (pD2) evoked by NE was reduced; such effect was reversed by TRPV1 blockade, and exacerbated by the TRPV4 antagonist. In RA of these animals, FA (Emax) evoked by NE was reduced by TRPC5 blockade, ML-204, and an increase in the expression (mRNA) of the receptors HCN4, TRPA1, TRPV1, b2 and b3 was observed but not of channels / proteins involved in Ca2+ homeostasis (eg, RyR2, Serca2a, Cav1.2). In the PA of these, a significant increase of the expression (mRNA) for factor Nrf2 was observed, and this effect was potentiated by TRPV1 blockade. Mice exposed to 1,2-NQ had no changes in caudal blood pressure, but exhibited changes in RR, SDRR, RMSSD, LF/HF ECG parameters, and phenylephrine (Phe) and ACh sensitivity in PA. Blockade of TRPV1 and TRPV4 exacerbated the effect of Phe and inhibited ACh response, respectively, in the PA of animals exposed to 1,2-NQ, and stimulated atrial fibrillation in the ouabain-induced model. In conclusion, these results show, for the first time, the molecular potential of TRP receptors (TRPV1) and b1 in functional alterations in RA and murine CV system in vitro incubation or in vivo neonatal exposure to 1,2-NQ, revealing the vulnerability of age to the adverse effects of 1,2-NQ. These functional and molecular findings also serve as indicators of susceptibility to the onset of CV dysfunctions elicited by 1,2- NQ.
 
There are withheld file due to requirements (data publishing, patents or rights).
Release Date
2024-04-08
Publishing Date
2021-10-13
 
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