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Acute and subchronic exposure to air particulate matter induces expression of angiotensin and bradykinin-related genes in the lungs and heart: Angiotensin-II type-I receptor as a molecular target of particulate matter exposure.

Aztatzi-Aguilar OG, Uribe-Ramírez M, Arias-Montaño JA, Barbier O, De Vizcaya-Ruiz A - Part Fibre Toxicol (2015)

Bottom Line: The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner.The AT1R lung protein showed a time-dependent change in subcellular distribution.In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, CP. 07360, Mexico. gammaztatzi@gmail.com.

ABSTRACT

Background: Particulate matter (PM) adverse effects on health include lung and heart damage. The renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) endocrine systems are involved in the pathophysiology of cardiovascular diseases and have been found to impact lung diseases. The aim of the present study was to evaluate whether PM exposure regulates elements of RAAS and KKS.

Methods: Sprague-Dawley rats were acutely (3 days) and subchronically (8 weeks) exposed to coarse (CP), fine (FP) or ultrafine (UFP) particulates using a particulate concentrator, and a control group exposed to filtered air (FA). We evaluated the mRNA of the RAAS components At1, At2r and Ace, and of the KKS components B1r, B2r and Klk-1 by RT-PCR in the lungs and heart. The ACE and AT1R protein were evaluated by Western blot, as were HO-1 and γGCSc as indicators of the antioxidant response and IL-6 levels as an inflammation marker. We performed a binding assay to determinate AT1R density in the lung, also the subcellular AT1R distribution in the lungs was evaluated. Finally, we performed a histological analysis of intramyocardial coronary arteries and the expression of markers of heart gene reprogramming (Acta1 and Col3a1).

Results: The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner. CP exposure induced Ace mRNA expression and regulated its protein in the lungs. Acute and subchronic exposure to FP and UFP induced the expression of At1r in the lungs and heart. All PM fractions increased the AT1R protein in a size-dependent manner in the lungs and heart after subchronic exposure. The AT1R lung protein showed a time-dependent change in subcellular distribution. In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6. Moreover, exposure to all PM fractions increased coronary artery wall thickness.

Conclusion: We demonstrate that exposure to PM induces the expression of RAAS and KKS elements, including AT1R, which was the main target in the lungs and the heart.

No MeSH data available.


Related in: MedlinePlus

Particulate matter induces lung AT1R and ACE mRNA in a size- and time-dependent manner. The animals were exposed to coarse (CP), fine (CP) and ultrafine particulate (UFP). A control group was exposed to filtered air (FA). The semi-quantitative levels of Angiotensin Receptor Type-1 (At1r) and Angiotensin-I Converting Enzyme (Ace) mRNA after acute (3 days, 5 h/d) and subchronic (8 weeks, 5 h/d, 4 d/week) exposure are shown. Scatter dot plot shows the value of the median. Below each graph representatives gels illustrating the expression levels of mRNA are shown. * indicates significant differences among groups (n = 4 per group, p < 0.05)
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Fig1: Particulate matter induces lung AT1R and ACE mRNA in a size- and time-dependent manner. The animals were exposed to coarse (CP), fine (CP) and ultrafine particulate (UFP). A control group was exposed to filtered air (FA). The semi-quantitative levels of Angiotensin Receptor Type-1 (At1r) and Angiotensin-I Converting Enzyme (Ace) mRNA after acute (3 days, 5 h/d) and subchronic (8 weeks, 5 h/d, 4 d/week) exposure are shown. Scatter dot plot shows the value of the median. Below each graph representatives gels illustrating the expression levels of mRNA are shown. * indicates significant differences among groups (n = 4 per group, p < 0.05)

Mentions: On the other hand, major and significant mRNA changes were observed for the At1r and Ace angiotensin system genes in the lungs. These are two of the most important genes in this system and are therapeutic targets in conditions such as hypertension (Fig. 1). For both periods of exposure, we found an increase in the levels of At1r mRNA in the groups exposed to FP and UFP compared with those exposed to FA (Fig. 1a and b). In contrast to the effects observed with FP and UFP fractions, we observed a decrease in At1r mRNA levels in the group subchronically exposed to CP (Fig. 1b). The At2r mRNA levels were not significantly different among any of the types of particle and exposure time conditions as shown in Table 1. Our results for the Ace mRNA levels showed a significant increment following the acute exposures to FP and UFP, but not for the subchronic exposures (Fig. 1c and d). On the other hand, the group exposed subchronically to CP responded with a large increase in the Ace mRNA relative to all other groups (Fig. 1d). It has been reported that RAAS elements can be expressed constitutively within the cells of various tissues and can have intracrine, paracrine and endocrine effects in the organism [10]. Angiotensin-II is the product of the enzymatic activity of ACE and is the ligand for AT1R and AT2R. Lung tissue expresses these three genes, which are important in the regulation of the pulmonary circulation. As a result of the exposures, At1r and Ace responded to PM, but At2r did not. This suggests that PM exposure modulates the activation of angiotensin-I and the deactivation of bradykinin by up-regulating Ace and promoting At1r up-regulation However, the regulation of At2r, which has been considered to have an antagonistic effect on the At1r signaling pathway, was not affected.Fig. 1


Acute and subchronic exposure to air particulate matter induces expression of angiotensin and bradykinin-related genes in the lungs and heart: Angiotensin-II type-I receptor as a molecular target of particulate matter exposure.

Aztatzi-Aguilar OG, Uribe-Ramírez M, Arias-Montaño JA, Barbier O, De Vizcaya-Ruiz A - Part Fibre Toxicol (2015)

Particulate matter induces lung AT1R and ACE mRNA in a size- and time-dependent manner. The animals were exposed to coarse (CP), fine (CP) and ultrafine particulate (UFP). A control group was exposed to filtered air (FA). The semi-quantitative levels of Angiotensin Receptor Type-1 (At1r) and Angiotensin-I Converting Enzyme (Ace) mRNA after acute (3 days, 5 h/d) and subchronic (8 weeks, 5 h/d, 4 d/week) exposure are shown. Scatter dot plot shows the value of the median. Below each graph representatives gels illustrating the expression levels of mRNA are shown. * indicates significant differences among groups (n = 4 per group, p < 0.05)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4482198&req=5

Fig1: Particulate matter induces lung AT1R and ACE mRNA in a size- and time-dependent manner. The animals were exposed to coarse (CP), fine (CP) and ultrafine particulate (UFP). A control group was exposed to filtered air (FA). The semi-quantitative levels of Angiotensin Receptor Type-1 (At1r) and Angiotensin-I Converting Enzyme (Ace) mRNA after acute (3 days, 5 h/d) and subchronic (8 weeks, 5 h/d, 4 d/week) exposure are shown. Scatter dot plot shows the value of the median. Below each graph representatives gels illustrating the expression levels of mRNA are shown. * indicates significant differences among groups (n = 4 per group, p < 0.05)
Mentions: On the other hand, major and significant mRNA changes were observed for the At1r and Ace angiotensin system genes in the lungs. These are two of the most important genes in this system and are therapeutic targets in conditions such as hypertension (Fig. 1). For both periods of exposure, we found an increase in the levels of At1r mRNA in the groups exposed to FP and UFP compared with those exposed to FA (Fig. 1a and b). In contrast to the effects observed with FP and UFP fractions, we observed a decrease in At1r mRNA levels in the group subchronically exposed to CP (Fig. 1b). The At2r mRNA levels were not significantly different among any of the types of particle and exposure time conditions as shown in Table 1. Our results for the Ace mRNA levels showed a significant increment following the acute exposures to FP and UFP, but not for the subchronic exposures (Fig. 1c and d). On the other hand, the group exposed subchronically to CP responded with a large increase in the Ace mRNA relative to all other groups (Fig. 1d). It has been reported that RAAS elements can be expressed constitutively within the cells of various tissues and can have intracrine, paracrine and endocrine effects in the organism [10]. Angiotensin-II is the product of the enzymatic activity of ACE and is the ligand for AT1R and AT2R. Lung tissue expresses these three genes, which are important in the regulation of the pulmonary circulation. As a result of the exposures, At1r and Ace responded to PM, but At2r did not. This suggests that PM exposure modulates the activation of angiotensin-I and the deactivation of bradykinin by up-regulating Ace and promoting At1r up-regulation However, the regulation of At2r, which has been considered to have an antagonistic effect on the At1r signaling pathway, was not affected.Fig. 1

Bottom Line: The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner.The AT1R lung protein showed a time-dependent change in subcellular distribution.In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, CP. 07360, Mexico. gammaztatzi@gmail.com.

ABSTRACT

Background: Particulate matter (PM) adverse effects on health include lung and heart damage. The renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) endocrine systems are involved in the pathophysiology of cardiovascular diseases and have been found to impact lung diseases. The aim of the present study was to evaluate whether PM exposure regulates elements of RAAS and KKS.

Methods: Sprague-Dawley rats were acutely (3 days) and subchronically (8 weeks) exposed to coarse (CP), fine (FP) or ultrafine (UFP) particulates using a particulate concentrator, and a control group exposed to filtered air (FA). We evaluated the mRNA of the RAAS components At1, At2r and Ace, and of the KKS components B1r, B2r and Klk-1 by RT-PCR in the lungs and heart. The ACE and AT1R protein were evaluated by Western blot, as were HO-1 and γGCSc as indicators of the antioxidant response and IL-6 levels as an inflammation marker. We performed a binding assay to determinate AT1R density in the lung, also the subcellular AT1R distribution in the lungs was evaluated. Finally, we performed a histological analysis of intramyocardial coronary arteries and the expression of markers of heart gene reprogramming (Acta1 and Col3a1).

Results: The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner. CP exposure induced Ace mRNA expression and regulated its protein in the lungs. Acute and subchronic exposure to FP and UFP induced the expression of At1r in the lungs and heart. All PM fractions increased the AT1R protein in a size-dependent manner in the lungs and heart after subchronic exposure. The AT1R lung protein showed a time-dependent change in subcellular distribution. In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6. Moreover, exposure to all PM fractions increased coronary artery wall thickness.

Conclusion: We demonstrate that exposure to PM induces the expression of RAAS and KKS elements, including AT1R, which was the main target in the lungs and the heart.

No MeSH data available.


Related in: MedlinePlus