ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good

Xu, Ping; Sriramula, Srinivas; Lazartigues, Eric

doi:10.1152/ajpregu.00222.2010

Cited by 241 publications

(264 citation statements)

References 162 publications

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“…The discovery of a new member within the RAS family, ACE2 , named due to 40% homology and 61% sequence similarity with ACE, by two different groups in 2000 (Donoghue et al, 2000;Tipnis et al, 2000) caused much excitement in the field of CVD pharmacotherapy. The main action of ACE2 is to shuttle Ang II and to tip the balance toward Ang (1-7) formation (Xu, Sriramula, & Lazartigues, 2011). Functionally, ACE2 is a pleiotropic monocarboxypeptidase and metabolizes a range of peptides (Zhong et al, 2010).…”

Section: Angiotensin IImentioning

confidence: 99%

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

Alghamri

Weir

Anstadt

et al. 2012

J Cardiovasc Pharmacol Ther

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Mahmoud Alghamri. M.S., Department of Pharmacology and Toxicology, Wright State University, 2012. Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice.Activation of the renin angiotensin system (RAS) is a well-known driving force, governing the aggravation and progression of CVD and associated target organ damage.Angiotensin (Ang) converting enzyme 2 (ACE2), a new member within the RAS family, was first cloned from the ventricle of patient with heart failure. ACE2 was shown to be upregulated under pathological conditions. We hypothesize that loss of ACE2 negatively affects cardiac function and exacerbates hypertrophic cardiomyopathy and aortic remodeling in response to Ang II. Eight weeks old ACE2 knock out (KO) and wild type (WT) mice were infused with Ang II s.c. (1000 ng/kg/min for 4 weeks) using osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography) and cardiac/aortic structural damage (histology) were examined. At baseline before Ang II, ACE2 KO displayed a normal phenotype for cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) was increased (~40% in WT and ~33% in ACE2 KO) with no differences between groups. However, ACE2 KO responded differently to the increased MAP. Cardiac function analysis revealed severe myocardial dysfunction shown by the lowered EF% (31% vs. 13%) as well as FS% (30% vs 6%) in ACE2 KO vs WT, respectively. In addition, the cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by the increased left ventricular wall thickness as well as heart weight/ body weight ratio. Moreover, collagen staining in the myocardium and aorta revealed higher collagen percentage in ACE2 KO which indicates iv cardiovascular remodeling. Furthermore, results showed enhanced oxidative stress in the myocardium and aorta of Ang II infused ACE2 KO compared to Ang II WT. In conclusion, ACE2 attenuates myocardial maladaptive hypertrophy and cardiovascular remodeling in response to long term Ang II stimulation.v

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Section: Angiotensin IImentioning

confidence: 99%

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

Alghamri

Weir

Anstadt

et al. 2012

J Cardiovasc Pharmacol Ther

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“…Intracrine, or intracellular forms of the RAS, have also been described (46,109). Although the generation and action of other angiotensin peptides in the brain (such as ANG [1][2][3][4][5][6][7] by ACE2) has garnered considerable attention (147), this review will focus primarily on ANG II.…”

mentioning

confidence: 99%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Coble JP, Grobe JL, Johnson AK, Sigmund CD. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regul Integr Comp Physiol 308: R238 -R249, 2015. First published December 17, 2014 doi:10.1152/ajpregu.00486.2014.-It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra-or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra-and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT 1R) and angiotensin type 2 receptors (AT 2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.angiotensin; blood pressure; barin; fluid; renin FLUID BALANCE is crucial for the homeostasis and survival of organisms because they have to properly maintain fluid and electrolyte concentrations for the normal function of all cells. Fluid balance can go awry in pathological states such as in chronic kidney disease and diabetes. Among its many roles in maintaining homeostasis, the renin-angiotensin system (RAS) is an important regulator of fluid balance. The RAS achieves this through the actions of its main effector peptide, angiotensin II (ANG II) through the ANG II type 1 (AT 1 R) and type 2 (AT 2 R) receptors. Activation of AT 1 R by blood-borne ANG II in target tissues causes increases in sodium and water retention, arginine vasopressin (AVP), and aldosterone release, vasoconstriction, increased sympathetic nervous system activity, and increased fluid intake. ANG II is produced by the consecutive enzymatic action of renin on its substrate angiotensinogen (AGT) and by angiotensin-converting enzyme (ACE) on its substrate angiotensin I (ANG I). The renin-AGT cleavage step is generally the rate-limiting step in the production of ANG II, and this is certainly true in the brain where the amount of renin is limiting. The RAS exists in two forms: a circulatory form where ANG II acts as an endocrine factor, and a tissue-specific form, where local production of ANG II acts in an autocrine or paracrine manner to induce AT 1 R signaling on ANG II producing or nearby cells (75). Intracrine, or intracellular forms of the RAS, hav...

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“…36,41,42 Their activation may protect from cerebral ischemia or hypertension. [43][44][45] Our findings in healthy humans show that intranasal ANGII combined with systemic AT1 receptor blockade reduces blood pressure. The present combination of treatments might have functioned to specifically activate brain AT2 receptors.…”

Section: Discussionmentioning

confidence: 63%

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

et al. 2014

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T he peptide hormone angiotensin II (ANGII) displays a wide range of regulatory actions on blood pressure. Besides its systemic effects on the blood vessels and different organ systems, local ANGII is crucially involved in the central nervous regulation of blood pressure.1-6 ANGII receptors, mainly type 1 receptors (AT1) and also type 2 receptors (AT2), are expressed in several cerebral nuclei where they mediate effects of locally produced ANGII.7-10 Inhibition of central nervous ANGII synthesis reversed hypertension in spontaneously hypertensive rats. 11The differentiation of central nervous and peripheral actions of ANGII is important for understanding blood pressure homeostasis and the development of essential hypertension in humans. Peripheral ANGII increases blood pressure but cannot surpass the blood-brain barrier, except via the circumventricular organs (area postrema, organum vasculosum laminae terminalis).12,13 These structures express a magnitude of AT1 receptors and seem to serve as an interface gating effects of circulating ANGII to brain stem and hypothalamic nuclei (ie, nucleus tractus solitarius, supraoptic nucleus, and paraventricular nuclei). Such humoral ANGII input is known to increase tonic blood pressure levels by an upward resetting of the sympathetic baroreceptor reflex activity 2,14-17 and may also activate intrinsic hypothalamic neurohypophysial fiber pathways, inducing the release of vasopressin. 3,[18][19][20] When ANGII is directly injected into the nucleus tractus solitarius, the baroreceptor reflex is suppressed via activation of AT1 receptors. After intracerebral administration, however, pressor effects of ANGII were revealed to be variable and even contradictory depending on dose and location of the injection, therefore suggesting differential effects on blood pressure regulation. 3,4,9,10,19,[21][22][23][24] The intranasal administration of small peptide molecules represents an established approach to bypass the bloodbrain barrier in humans and to achieve direct central nervous effects. [25][26][27][28][29] These studies demonstrate that peptide molecules such as ANGII directly enter the cerebrospinal fluid after their intranasal administration without previous uptake to the blood but instead via diffusion along neuronal clefts in the nasal mucosa. Importantly, because of the relatively great amounts of substance administered to achieve central nervous effects of the peptide, it cannot be prevented that, rather than directly accessing the cerebrospinal fluid compartment, some portion of the substance spills over into the circulation. Peptide that enters the circulation might then mask direct central nervous effects after intranasal peptide administration. Thus, a viable approach to unravel direct brain effects of intranasal peptide administration is to combine this treatment with a peripherally acting receptor blocker of the peptide.Abstract-Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different from intravenously administered ANGII via a d...

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ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good

Cited by 241 publications

References 162 publications

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

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