Abstract TMP58: Post Stroke Activation of Angiotensin II Type 2 Receptors Shows Sustained Neuroprotective Effects in Aged Rats

Background: The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2Rs). Compound 21 (C21), a selective non-peptide AT2R agonist, has been shown to exhibit neuroprotection and improve stroke outcomes in preclinical studies. Stimulation of AT2Rs is believed to counteract the negative effects of angiotensin type 1 receptor and provide distinctive beneficial anti-inflammatory and neurotropic effects. We hypothesized that C21 given after stroke through peripheral injections would have sustained neuroprotective effects in aged rats. Methods: Aged adult male SD rats (18-20 months) underwent ischemic stroke by monofilament middle cerebral artery occlusion (MCAO) and were randomly divided into two groups that received intraperitoneal (IP) injections of either 0.9% NaCl or 0.03mg/kg C21 at reperfusion (90 min), 24h, and 48h after stroke. All animals received blinded neurological exams at 4h, 24h, 72h, 7d, 14d, and 21d post-stroke. Infarct size was assessed by magnetic resonance imaging at 21 days. Results: Post-stroke treatment with C21 significantly improved neurological function, as evidenced by neurological testing using Rotarod and somatosensory dysfunction exams. At 7d and 14d after stroke, C21-treated rats had significantly increased Rotarod times versus saline-treated rats, and at 21d, the somatosensory function was significantly improved as measured by time to removal of paw adhesive. Infarct volume tended to be non-significantly decreased by C21 treatment at 21d post-stroke. Conclusions: Our findings indicate that targeting the renin-angiotensin system, specifically by stimulation of AT2Rs with C21, improves neurological function in aged rats with stroke over a sustained period of 21 days. These findings encourage further research into the renin-angiotensin system and specifically AT2Rs, and offers hope for effective alternatives for treating stroke.

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390 Characterization of the Renin-Angiotensin System Regulation in Cavernosal Tissue of Aged Rats

Journal of Sexual Medicine ◽

10.1016/j.jsxm.2016.11.269 ◽

2017 ◽

Vol 14 (1) ◽

pp. S115-S116

Author(s):

M.E. Bragina ◽

R.A. Fraga-Silva ◽

F.P. Costa-Fraga ◽

N. Stergiopulos

Keyword(s):

Renin Angiotensin System ◽

Aged Rats ◽

Angiotensin System ◽

Renin Angiotensin

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Abstract TP111: Activation of the Brain Renin-Angiotensin System by Translational Approaches Following Stroke Onset Is Neuroprotective in a Rat Model of Ischemic Stroke

Stroke ◽

10.1161/str.44.suppl_1.atp111 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Douglas M Bennion ◽

Lauren Donnangelo ◽

David Pioquinto ◽

Robert Regenhardt ◽

Mohan K Raizada ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Renin Angiotensin System ◽

Cerebral Infarct ◽

Intraventricular Administration ◽

Angiotensin System ◽

Renin Angiotensin ◽

Post Stroke ◽

Neurologic Deficits ◽

The Brain

Background: Toward discovering novel stroke therapies, recent research has shown that activation of the newly-discovered angiotensin converting enzyme 2/angiotensin-(1-7)/mas (ACE2/Ang-(1-7)/Mas) pathway, a counter-regulatory axis of the brain renin-angiotensin system, is neuroprotective in ischemic stroke in rats. Specifically, intraventricular administration of the novel ACE2 activator diminazine aceturate (DIZE) before and during an ischemic stroke decreases cerebral infarct and neurologic deficits. Efficacy must now be demonstrated using minimally-invasive methods if this therapy is to be translated to the care of human patients. In this study, we assessed the hypothesis that systemic administration of DIZE post ischemic stroke would be neuroprotective. Methods: Adult male Sprague-Dawley rats underwent ischemic stroke by endothelin-1 induced middle cerebral artery occlusion and were randomly divided into 2 groups (n=9-10/set): 1) intraperitoneal (IP) administrations of DIZE (7.5 mg/kg) at 4, 24, and 48 h after stroke; 2) IP administrations of 0.9% saline vehicle at the same time points. At 24 and 72 h after stroke, rats underwent blinded neurologic assessments. Immediately following the 72 h tests, animals were sacrificed, cerebral infarct volumes assessed by TTC staining, and IL-1β expression in the stroke region analyzed by rt-PCR. Data are expressed as mean ± SEM with significance inferred at p<0.05. Results: Mean infarct volume was significantly decreased by IP injections of DIZE (9.4% ± 4.35) as compared to control (22.8%±3.6, p=0.039). At 24 h post stroke, neurologic deficits (Garcia Scale) were significantly improved in the DIZE treated group (16.7±0.40) versus the saline group (15.22±0.57, p=0.037). Although DIZE tended to improve neurologic deficits 72 h post stroke, this trend was not significant. Finally, DIZE treatment significantly reduced mRNA expression of IL-1β (0.43 ± 0.14) in the cerebral cortical stroke region as compared to saline treatment (1.47±0.08, p=0.001). Conclusions: Our findings suggest that targeting the ACE2/Ang-(1-7)/Mas axis post stroke can improve function, decrease inflammation, and reduce infarct volume - a significant translational step in brain renin-angiotensin system research.

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The renin–angiotensin system, bone marrow and progenitor cells

Clinical Science ◽

10.1042/cs20110660 ◽

2012 ◽

Vol 123 (4) ◽

pp. 205-223 ◽

Cited By ~ 48

Author(s):

Matej Durik ◽

Bruno Sevá Pessôa ◽

Anton J. M. Roks

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Angiotensin Ii ◽

Progenitor Cells ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Cardiovascular Therapy ◽

Cardiovascular Cells ◽

Stimulation Of

Modulation of the RAS (renin–angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1–7) [angiotensin-(1–7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT1 receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT2 receptor (angiotensin II type 2 receptor) and the Ang-(1–7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1–7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications.

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Local renin-angiotensin system regulates the differentiation of mesenchymal stem cells into insulin-producing cells through angiotensin type 2 receptor

Biochimie ◽

10.1016/j.biochi.2017.03.002 ◽

2017 ◽

Vol 137 ◽

pp. 132-138 ◽

Cited By ~ 6

Author(s):

Nermin Abdel-hamid Sadik ◽

Nadia Said Metwally ◽

Olfat Gamil Shaker ◽

Mahmoud Sanad Soliman ◽

Ahmed Abdelaziz Mohamed ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Insulin Producing Cells ◽

Angiotensin Type 2 Receptor ◽

Angiotensin Type

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Stimulation of the renin-angiotensin system and drinking by papaverine in the seawater eel,Anguilla anguilla

Journal of Fish Biology ◽

10.1006/jfbi.1995.0064 ◽

1995 ◽

Vol 46 (4) ◽

pp. 721-724

Author(s):

M Tierney

Keyword(s):

Renin Angiotensin System ◽

Anguilla Anguilla ◽

Angiotensin System ◽

Renin Angiotensin ◽

Stimulation Of

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Chymase-dependent production of angiotensin II: an old enzyme in old hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00534.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. H223-H231 ◽

Cited By ~ 17

Author(s):

Ghezal Froogh ◽

John T. Pinto ◽

Yicong Le ◽

Sharath Kandhi ◽

Yeabsra Aleligne ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Ang Ii ◽

Aged Rats ◽

Converting Enzyme ◽

Local Formation ◽

Angiotensin System ◽

Renin Angiotensin ◽

Age Dependent

Age-dependent alteration of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) are well documented. By contrast, RAS-independent generation of Ang II in aging and its responses to exercise have not been explored. To this end, we examined the effects of chymase, a secretory serine protease, on the angiotensin-converting enzyme (ACE)-independent conversion of Ang I to Ang II. We hypothesized that age-dependent alteration of cardiac Ang II formation is chymase dependent in nature and is prevented by exercise training. Experiments were conducted on hearts isolated from young (3 mo), aged sedentary (24 mo), and aged rats chronically exercised on a treadmill. In the presence of low Ang I levels and downregulation of ACE expression/activity, cardiac Ang II levels were significantly higher in aged than young rats, suggesting an ACE-independent response. Aged hearts also displayed significantly increased chymase expression and activity, as well as upregulation of tryptase, a biological marker of mast cells, confirming a mast cell-sourced increase in chymase. Coincidently, cardiac superoxide produced from NADPH oxidase (Nox) was significantly enhanced in aged rats and was normalized by exercise. Conversely, a significant reduction in cardiac expression of ACE2 followed by lower Ang 1-7 levels and downregulation of the Mas receptor (binding protein of Ang 1-7) in aged rats were completely reversed by exercise. In conclusion, local formation of Ang II is increased in aged hearts, and chymase is primarily responsible for this increase. Chronic exercise is able to normalize the age-dependent alterations via compromising chymase/Ang II/angiotensin type 1 receptor/Nox actions while promoting ACE2/Ang 1-7/MasR signaling. NEW & NOTEWORTHY Aging increases angiotensin-converting enzyme (ACE)-independent production of cardiac angiotensin II (Ang II), a response that is driven by chymase in an exercise-reversible manner. These findings highlight chymase, in addition to ACE, as an important therapeutic target in the treatment and prevention of Ang II-induced deterioration of cardiac function in the elderly. Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/renin-angiotensin-system-signaling-in-aged-and-age-exercised-rats/ .

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Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function.

Circulation ◽

10.1161/01.cir.87.6.1969 ◽

1993 ◽

Vol 87 (6) ◽

pp. 1969-1973 ◽

Cited By ~ 251

Author(s):

P M Ridker ◽

C L Gaboury ◽

P R Conlin ◽

E W Seely ◽

G H Williams ◽

...

Keyword(s):

Angiotensin Ii ◽

Plasminogen Activator ◽

Renin Angiotensin System ◽

Plasminogen Activator Inhibitor ◽

Potential Interaction ◽

Angiotensin System ◽

Renin Angiotensin ◽

Activator Inhibitor ◽

Stimulation Of

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Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition

AJP Renal Physiology ◽

10.1152/ajprenal.00477.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. F150-F157 ◽

Cited By ~ 48

Author(s):

Romer A. Gonzalez-Villalobos ◽

Ryousuke Satou ◽

Naro Ohashi ◽

Laura C. Semprun-Prieto ◽

Akemi Katsurada ◽

...

Keyword(s):

Renin Angiotensin System ◽

Ace Inhibition ◽

Ang Ii ◽

Male Mice ◽

Rt Pcr ◽

Angiotensin System ◽

Renin Angiotensin ◽

Induced Hypertension ◽

Angiotensin Type

Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT1R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9–12 wk old) were distributed as controls ( n = 10), ANG II infused (ANG II = 8, 400 ng·kg−1·min−1 for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 ± 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 ± 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 ± 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 ± 0.07, P < 0.05) or in combination with ANG II (0.80 ± 0.07, P < 0.05). AT1R protein (by WB) was increased by ANG II (1.27 ± 0.06, P < 0.05) and ACEi (1.17 ± 0.06, P < 0.05) but not ANG II + ACEi [1.15 ± 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 ± 0.23, P < 0.05) and ACEi (1.57 ± 0.15, P < 0.05), but not ANG II + ACEi (1.10 ± 0.15, NS). No significant changes were observed in AGT, ACE, or AT1R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT1R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension.

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