A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression

Haga, Shiori; Tsuchiya, Haruka; Hirai, Toshitake; Hamano, Takaichi; Matsubara, Akio; Ishizaka, Yukihito

doi:10.3109/01902148.2014.959141

Cited by 42 publications

(34 citation statements)

References 43 publications

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“…Furthermore, DIZE failed to elicit beneficial effects on cholesterol metabolism and abdominal aortic aneurysms in ACE2-KO mice 152 . The recent discovery of a novel ACE2 activator, NCP-2454, provides additional support for the idea that ACE2 activators do indeed enhance activation of ACE2 both in vitro and in vivo 155 . This mountain of data provides evidence that these compounds are, indeed, ACE2 activators.…”

Section: Ace2 Activatorsmentioning

confidence: 92%

ACE2 and Microbiota

Cole‐Jeffrey

Katovich

et al. 2015

Journal of Cardiovascular Pharmacology

101

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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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Section: Ace2 Activatorsmentioning

confidence: 92%

ACE2 and Microbiota

Cole‐Jeffrey

Katovich

et al. 2015

Journal of Cardiovascular Pharmacology

101

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“…MCT-induced pulmonary hypertension was developed by a single subcutaneous injection of MCT (60 mg/kg) [18,19] , whereas animals in the control group were simultaneously injected with physiological saline. Salvianolic acid A (0.3, 1, and 3 mg·kg -1 ·d -1 , dissolved in saline) or bosentan (30 mg·kg -1 ·d -1 , suspended in saline) was orally administered every day for 4 weeks after MCT injection, whereas the control and model groups received the same volume of physiological saline.…”

Section: Experimental Protocol and Drug Administrationmentioning

confidence: 99%

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Chen¹,

Yuan²,

Zhang³

et al. 2016

Acta Pharmacol Sin

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Aim:The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling, which is characteristic of pulmonary arterial hypertension (PAH). In this study we examined whether salvianolic acid A (SAA) extracted from the traditional Chinese medicine 'Dan Shen' attenuated vascular remodeling in a PAH rat model, and elucidated the underlying mechanisms. Methods: PAH was induced in rats by injecting a single dose of monocrotaline (MCT 60 mg/kg, sc). The rats were orally treated with either SAA (0.3, 1, 3 mg·kg -1 ·d -1 ) or a positive control bosentan (30 mg·kg -1 ·d -1 ) for 4 weeks. Echocardiography and hemodynamic measurements were performed on d 28. Then the hearts and lungs were harvested, the organ indices and pulmonary artery wall thickness were calculated, and biochemical and histochemical analysis were conducted. The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting. Results: Treatment with SAA or bosentan effectively ameliorated MCT-induced pulmonary artery remodeling, pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure (RVSP). Furthermore, the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium, parenchymal injury and collagen deposition in the lungs. Moreover, the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs. The treatments partially restored MCT-induced reductions of bone morphogenetic protein type II receptor (BMPRII) and phosphorylated Smad1/5 in the lungs. Conclusion: SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRII-Smad pathway and inhibiting apoptosis. Thus, SAA may have therapeutic potential for the patients at high risk of PAH.

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“…Food-derived peptides can also inhibit ACE and renin. Flaxseed protein fractions, pea hydrolysates and hemp seed protein isolates have been reported to exhibit renin-inhibitory activities (111). The mechanisms of action of these peptides may depend on their structural features (90).…”

Section: Hypertensive Activity and Functional Foodsmentioning

confidence: 99%

Role of the ACE2-Ang-(1-7)-Mas axis in blood pressure regulation and its potential as an antihypertensive in functional foods

Lin

Pan

et al. 2017

Molecular Medicine Reports

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The renin‑angiotensin system (RAS) serves a critical role in blood pressure regulation and prevention of cardiovascular diseases. Efforts to develop functional foods that enhance the RAS have focused on inhibition of angiotensin‑converting enzyme (ACE) activity in the ACE‑angiotensin II (Ang II)‑Ang II type 1 receptor axis. ACE2 and the Mas receptor are important components of this axis. ACE2 catalyzes Ang II into Ang‑(1‑7), which then binds to the G‑protein‑coupled receptor Mas. In addition, it induces nitric oxide release from endothelial cells and exerts antiproliferative, vasodilatory and antihypertensive effects. The present review examined recent findings regarding the physiological and biological roles of the ACE2‑Ang‑(1‑7)‑Mas axis in the cardiovascular system, discussed potential food‑derived ACE2‑activating agents, and highlighted initiatives, based on this axis, that aim to develop functional foods for the treatment of hypertension.

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A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression

Abstract: NCP-2454 prevented MCT-induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression.

Cited by 42 publications

References 43 publications

ACE2 and Microbiota

ACE2 and Microbiota

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Role of the ACE2-Ang-(1-7)-Mas axis in blood pressure regulation and its potential as an antihypertensive in functional foods

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