Activation of renin–angiotensin–aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats

Yuan, Yujia; Luo, Li; Guo, Zhen; Yang, Ming; Ye, Ren-song; Luo, Chi‐Cheng

doi:10.1177/1470320315576256

Cited by 68 publications

(60 citation statements)

References 22 publications

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“…In our model, we found elevated lung concentrations of Ang II in aged female PSGL‐1 −/− mice. Thus, hypoxic and monocrotaline‐treated rats showed increased Ang II and AT 1 R levels , and patients with PAH showed higher levels of pulmonary Ang II due to increased activity of ACE, as well as increased expression and signaling of AT 1 R, resulting in augmented vascular smooth muscle cell (VSMC) proliferation . Inhibitors of the renin–angiotensin–aldosterone system (RAAS) have been shown to have an effect in reducing PAP and other PAH signs in some animal models and in pilot studies with small patient cohorts, highlighting the role of RAAS in the pathology of PAH.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

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Objective Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and noncurative treatments. As mice deficient in P‐selectin glycoprotein ligand 1 (PSGL‐1) develop a spontaneous SSc‐like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved. Methods Doppler echocardiography was used to estimate pulmonary pressure, immunohistochemistry was used to assess vascular remodeling, and myography of dissected pulmonary artery rings was used to analyze vascular reactivity. Angiotensin II (Ang II) levels were quantified by enzyme‐linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT1R), AT2R, endothelial cell nitric oxide synthase (eNOS), and phosphorylated eNOS expression in lung lysates. Flow cytometry allowed us to determine cytokine production by immune cells and NO production by endothelial cells. In all cases, there were 4–8 mice per experimental group. Results PSGL‐1−/− mice showed lung vessel wall remodeling and a reduced mean ± SD expression of pulmonary AT2R (expression ratio [relative to β‐actin] in female mice age >18 months: wild‐type mice 0.799 ± 0.508 versus knockout mice 0.346 ± 0.229). With aging, female PSGL‐1−/− mice had impaired up‐regulation of estrogen receptor α (ERα) and developed lung vascular endothelial dysfunction coinciding with an increase in mean ± SEM pulmonary Ang II levels (wild‐type 48.70 ± 5.13 pg/gm lung tissue versus knockout 78.02 ± 28.09 pg/gm lung tissue) and a decrease in eNOS phosphorylation, leading to reduced endothelial NO production. These events led to a reduction in the pulmonary artery acceleration time:ejection time ratio in 33% of aged female PSGL‐1−/− mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon‐γ–producing PSGL‐1−/− T cells and B cells and a reduced presence of regulatory T cells. Conclusion The absence of PSGL‐1 induces a reduction in Treg cells, NO production, and ERα expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.

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Section: Discussionmentioning

confidence: 99%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

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“…The arteriole expression of ACE is consistent with the hypothesis that locally increased production of ANG II contributes to the process of pulmonary vascular remodeling in PAH. In chronic cigarette smoke-induced PAH in rats, ANG II level in the lung was increased with increased expression of ACE and decreased expression of ACE2 (60,148). The decreased expression of ACE2 in pulmonary artery smooth muscle cells from cigarette smoke-exposed rats correlated with increased proliferation (60).…”

Section: Nicotine and The Ras In The Lungmentioning

confidence: 94%

“…The decreased expression of ACE2 in pulmonary artery smooth muscle cells from cigarette smoke-exposed rats correlated with increased proliferation (60). In addition, losartan administration in vivo reduced ANG II level in the lung, restored ACE2 expression, and ameliorated pulmonary vascular remodeling and smoke-induced increase in right ventricular systolic pressure (60,148). Koka et al (81) showed that ANG II downregulates ACE2 via AT 1 R-mediated extracellular signal-regulated kinase (ERK)/p38 MAPK signaling pathways; thus the decreased ACE2 expression by chronic cigarette smoke exposure could be mediated by a mechanism dependent on ANG II and AT 1 R. Cigarette smoke exposure in mice also increases ACE expression in the lung, and this upregulation was greater in ACE2 knockout mice compared with the wild-type controls (69).…”

Section: Nicotine and The Ras In The Lungmentioning

confidence: 97%

Nicotine and the renin-angiotensin system

Oakes

Fuchs

Gardner

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

275

268

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Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases (CVPD). Although cigarette smoking has been in constant decline since the 1950's, the introduction of e-cigarettes or electronic nicotine delivery systems 10 years ago has attracted former smokers as well as a new generation of consumers. Nicotine is a highly addictive substance, and it is currently unclear whether e-cigarettes are "safer" than regular cigarettes or whether they have the potential to reverse the health benefits, notably on the cardiopulmonary system, acquired with the decline of tobacco smoking. Of great concern, nicotine inhalation devices are becoming popular among young adults and youths, emphasizing the need for awareness and further study of the potential cardiopulmonary risks of nicotine and associated products. This review focuses on the interaction between nicotine and the renin-angiotensin system (RAS), one of the most important regulatory systems on autonomic, cardiovascular and pulmonary functions in both health and disease. The literature presented in this review strongly suggests that nicotine alters the homeostasis of the RAS by up-regulating the detrimental angiotensin converting enzyme (ACE)/Angiotensin (Ang)-II/Ang-II type 1 receptor (ATR) axis and down-regulating the compensatory ACE2/Ang-(1-7)/Mas receptor axis, contributing to the development of CVPD.

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“…A growing body of work has focused on the importance of ACE2 in PAH and associated right HF. Decreased lung ACE2 expression 79,80 and enzymatic activity 81 , along with increased circulating Ang II levels 82 , have been observed in PAH. Additionally, reduction in circulating ACE2 and Ang-(1-7) levels has been observed in patients with PAH from congenital HD 83,84 .…”

Section: Ace2 In Pulmonary Arterial Hypertensionmentioning

confidence: 99%

ACE2 and Microbiota

Cole‐Jeffrey

Katovich

et al. 2015

Journal of Cardiovascular Pharmacology

102

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The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (ACE/Ang II/AT1R) and vasoprotective (ACE2/Ang-(1–7)/MasR) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1–7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. While multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggests that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health.

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Activation of renin–angiotensin–aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats

Cited by 68 publications

References 22 publications

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Nicotine and the renin-angiotensin system

ACE2 and Microbiota

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