ACE2 Activation Confers Endothelial Protection and Attenuates Neointimal Lesions in Prevention of Severe Pulmonary Arterial Hypertension in Rats

Li, Gang; Liu, Yinglong; Zhu, Yaobin; Liu, Aijun; Xu, Yun; Li, Xiaofeng; Liu, Zhiqiang; Su, Junwu; Sun, Lu

doi:10.1007/s00408-013-9470-8

Cited by 60 publications

(47 citation statements)

References 26 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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“…It was very recently demonstrated that application of Ang-(1-7) into the RVLM resulted in complete attenuation of the detrimental stroke-induced pressor response as well as preventing increased heart rate [19]. In addition to a vasodilatory role, the vasoprotection conferred to the endothelium by activation of the ACE2–Ang-(1-7)–Mas axis has been abundantly demonstrated in the context of exercise [58], aging [16], pulmonary hypertension [59, 60], atherosclerosis [61], and vascular remodeling [53], to name a few. In line with these findings, several recent lines of evidence indicate an angiogenic role for the Ang-(1-7)–Mas system in stroke.…”

Section: Mechanisms Of Ang-(1-7)-induced Neuroprotectionmentioning

confidence: 99%

Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke

et al. 2015

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The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2–angiotensin-(1-7)–Mas axis [ACE2–Ang-(1-7)–Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that describe the protective role of the ACE2–Ang-(1-7)–Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II (AngII) via its type 1 receptor, including anti-inflammatory, anti-oxidant, vasodilatory, and angiogenic effects, and the role of altered kinase–phosphatase signaling. Interactions of Mas with other receptors, including bradykinin receptors and AngII type 2 receptors are also considered. A more complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting.

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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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ACE2 Activation Confers Endothelial Protection and Attenuates Neointimal Lesions in Prevention of Severe Pulmonary Arterial Hypertension in Rats

Abstract: These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system.

Cited by 60 publications

References 26 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

Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke

ACE2 and Microbiota

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