Angiotensin-(1-9) reduces cardiovascular and renal inflammation in experimental renin-independent hypertension

González, López; Novoa, Ulises; Moya, Jackeline; Gabrielli, Luigi; Jalil, Jorge; Garcı́a, Lorena; Chiong, Mario; Lavandero, Sergio; Ocaranza, María Paz

doi:10.1016/j.bcp.2018.08.045

Cited by 38 publications

(26 citation statements)

References 59 publications

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“…The first clinical trial of angiotensin 1-7 assessed the effect of this peptide on the reduction of blood flow in solid tumours 154 , whereas the first trial of aCe2 evaluated the safety and tolerability of a recombinant form of aCe2 121 . The anti-hypertrophic 135 , anti-hypertensive 73 , anti-inflammatory 120 and cardioprotective 6 properties of angiotensin 1-9 have been described. alamandine was discovered in 2013 as an anti-hypertensive agent 67 , and the cardioprotective properties of this compound have since been described 155,156 .…”

Section: Box 1 | Timeline Of the Discoveries Related To The Counter-rmentioning

confidence: 99%

Counter-regulatory renin–angiotensin system in cardiovascular disease

et al. 2019

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| The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and IIinitially thought to be biologically inactive -have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7 , angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT 2 R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical reninangiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review , we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

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Section: Box 1 | Timeline Of the Discoveries Related To The Counter-rmentioning

confidence: 99%

Counter-regulatory renin–angiotensin system in cardiovascular disease

et al. 2019

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“…An anti-inflammatory effect in vasculature, i.e. a reduction in monocyte infiltration in aortas from deoxycorticosterone acetate-hypertensive rats, has also been shown for the ACE2-dependent, endogenous AT 2 R-agonist Ang-1-9 [135]. Notably, both studies identified AT 2 R-mediated, anti-inflammatory effects, which specifically counteracted pro-inflammatory mechanisms relevant for COVID-19-associated endothelial injury.…”

Section: Endothelial Protection and Anti-coagulationmentioning

confidence: 75%

Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists

Steckelings

Sumners

2020

Clinical Science

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin–angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.

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“…The administration of Ang 1-9 led to decreased ACE activity and reduced Ang II formation in the hearts of diabetic rats [104]. In the rat DOCA-salt model of hypertension, Ang 1-9 attenuated inflammation and protected against organ fibrosis in the heart, aorta and kidney [105]. In experimental pulmonary hypertension in rats, Ang 1-9 reduced plasma levels of inflammatory cytokines, such as TNF-α, MCP-1, IL-1β and IL-6, and reversed changes in the expression of apoptosis-related proteins, such as Bax, Bcl-2, Caspase-3 and -9 in the lungs [106].…”

Section: Other Non-classical Ras Componentsmentioning

confidence: 98%

Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome

Hrenak

Šimko

2020

IJMS

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Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin–angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg9-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1–9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin–angiotensin system and reducing the pathogen’s cell entry could be a promising therapeutic strategy in the struggle against COVID-19.

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Angiotensin-(1-9) reduces cardiovascular and renal inflammation in experimental renin-independent hypertension

Cited by 38 publications

References 59 publications

Counter-regulatory renin–angiotensin system in cardiovascular disease

Counter-regulatory renin–angiotensin system in cardiovascular disease

Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists

Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome

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