Activation of angiotensin-(1–7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats
Introduction
The renin–angiotensin system (RAS) plays a key role in the control of arterial pressure (AP) and hydroelectrolytic balance (Hall, 1991). However, the inappropriate overactivity of the angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/AT1 receptor axis is critically involved in the pathogenesis of cardiovascular diseases. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis can counterbalance and attenuate the deleterious actions of Ang II (Ferrario et al., 2010, Santos, 2014). It is well known that increase in circulating levels of Ang-(1–7) induces important cardioprotective actions mediated by Mas receptor (Ferrario et al., 2010, Santos, 2014). Ang-(1–7) is capable to induce antiarrhythmogenic effect against ischemia/reperfusion injuries in rats (Ferreira et al., 2001, Santos, 2014), as well as, to prevent atrial tachycardia and fibrillation in rats and dogs (Ferreira et al., 2011, Liu et al., 2011), cardiac hypertrophy and Ang II-induced pathological cardiac remodeling (Santos, 2014).
In the brain, Ang-(1–7) is a powerful facilitator of the bradycardic component of the baroreflex control of heart rate (HR) in normotensive (Campagnole-Santos et al., 1992, Santos, 2014) or hypertensive animals (Benter et al., 1995, Britto et al., 1997, Heringer-Walther et al., 2001, Oliveira et al., 1996). ICV infusion of Ang-(1–7) inhibits sympathetic outflow and increases vagal outflow in rabbits with chronic heart failure, thus contributing to enhanced baroreflex gain in this condition (Kar et al., 2011). In addition, ICV infusion of Ang-(1–7) for 4 weeks significantly reduces the expression of Ang II and AT1 receptors in the brain of spontaneous hypertensive rats (Jiang et al., 2013).
We have previously shown that chronic ICV infusion of Ang-(1–7) attenuated hypertension and prevented the increase in collagen type I mRNA expression, normalized the baroreflex control of the AP and the autonomic tone to the heart in DOCA-salt rats (Guimaraes et al., 2012). Similarly, selective overexpression of ACE2 throughout the brain attenuated neurogenic hypertension (Feng et al., 2010). Moreover, ACE2 gene therapy in the paraventricular nucleus of the hypothalamus in mice prevented Ang II mediated oxidative stress in the brain and restored autonomic dysfunction (Xia et al., 2011). The actions of Ang-(1–7) in the brain seems to be mostly mediated by Mas receptor (Santos et al., 2005) which was shown to be expressed in cardiovascular-related areas in the central nervous system (Becker et al., 2007, Freund et al., 2012).
More recently, Xue et al. (2013) showed that ICV infusion of A779, a selective Mas receptor antagonist (Santos et al., 1994) significantly augmented the blood pressure of DOCA-salt induced hypertension in female rats. Moreover these authors showed that ICV Ang-(1–7) infusion attenuated the increased blood pressure observed after ovariectomy in female DOCA-salt rats (Xue et al., 2013).
Transgenic model of renin-dependent hypertension created by insertion of the mouse Ren-2 gene into the rat genome, the transgenic (mRen2)27 hypertensive rats (Mullins et al., 1990), exhibit high levels of Ang II in the brain and develop hypertension at early age (Mullins et al., 1990). Elevated Ang II/Ang-(1–7) ratio in the medulla of transgenic (mRen2)27 hypertensive rats (Senanayake et al., 1994) is accompanied by impaired baroreflex function (Diz et al., 2008). Furthermore, these rats exhibit cardiac fibrosis, remodeling, hypertrophy and cardiac dysfunction (Langheinrich et al., 1996). Previous studies showed that ICV administration (Dobruch et al., 2003) of Ang-(1–7) or the delivery of an Ang-(1–7) fusion protein in the cisterna magna (Garcia-Espinosa et al., 2012) attenuated the hypertension of (mRen2)27 hypertensive rats.
Considering that Ang-(1–7) lowers blood pressure, we hypothesized that chronic increase in Ang-(1–7) levels in the brain could ameliorate cardiac disorders observed in transgenic (mRen2)27 hypertensive rats through actions on Mas receptor. To address this hypothesis, we evaluated the cardiovascular parameters in (mRen2)27 rats subjected to chronic intracerebroventricular (ICV) infusion of Ang-(1–7) or Ang-(1–7) with the selective Mas receptor antagonist.
Section snippets
Material and methods
The procedures used for: blood pressure monitoring, ICV infusion, baroreflex test, cardiac autonomic tone evaluation, echocardiography, histological analysis, measurement of ACE and ACE2 activity, angiotensin levels, AT1 and Mas receptor protein expression, ANP, BNP, TGF-β levels and mRNA expression of components of the extracellular matrix are described only in the online Data Supplement.
Baseline systolic, diastolic, mean arterial pressure and heart rate
As shown in Fig. 1, conscious freely moving (mRen-2)27rats presented higher baseline SBP, DBP and HR compared to SD rats (n = 5). As expected, (mRen2)27-A7 showed a significant attenuation of hypertension [SBP = 168 ± 10 mmHg vs. 201 ± 3 mmHg in (mRen-2)27; or ΔMAP = −26 ± 4 mmHg in comparison to baseline, n = 6 each, Fig. 1A–C] and normalized baseline HR (372 ± 6 beats/min vs. 392 ± 6 beats/min, mmHg in (mRen-2)27; Fig. 1D). Furthermore, the co-infusion with A779 reversed the beneficial
Discussion
In the present study we showed that ICV infusion of Ang-(1–7) in transgenic (mRen-2)27 hypertensive rats reduced blood pressure, normalized the baroreflex control of HR, restored cardiac autonomic balance, reduced cardiac hypertrophy and pre-fibrotic lesions and decreased the altered imbalance of Ang II/Ang-(1–7) in the heart. Furthermore, most of these effects were mediated by Mas receptor in the brain, since were blocked by its selective antagonist, A779. Our data extended previous
Funding
This study was funded by Conselho Nacional de Ciência e Tecnologia (CNPq) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) through the following grants: PRONEX–CBB-APQ-04758-10 and INCT-NanoBiofar. LMK was a recipient of a fellowship from CAPES.
Conflicts of interest
The authors declare to have no conflicts of interest.
Acknowledgments
We are thankful to Marilene L. Oliveira, José Roberto da Silva, Bônia Alves and Mônica Alves for skillful technical assistance. This study is part of L. M. Kangussu doctoral thesis at the Graduate Program in Biological Sciences: Physiology and Pharmacology of the Federal University of Minas Gerais (UFMG).
References (44)
- et al.
Altered cardiovascular reflexes responses in conscious angiotensin-(1-7) receptor Mas-knockout mice
Peptides
(2010) - et al.
Advances in the renin angiotensin system focus on angiotensin-converting enzyme 2 and angiotensin-(1-7)
Adv. Pharmacol.
(2010) - et al.
Angiotensin-(1-7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats
Pharmacol. Res.
(2013) - et al.
The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects
Am. J. Hypertens.
(1996) - et al.
Enalapril, irbesartan, and angiotensin-(1-7) prevent atrial tachycardia-induced ionic remodeling
Int. J. Cardiol.
(2011) - et al.
Angiotensin-(1-7) binding at angiotensin II receptors in the rat brain
Regul. Pept.
(1995) - et al.
Characterization of a new angiotensin antagonist selective for angiotensin-(1-7): evidence that the actions of angiotensin-(1-7) are mediated by specific angiotensin receptors
Brain Res. Bull.
(1994) - et al.
Immunofluorescence localization of the receptor Mas in cardiovascular-related areas of the rat brain
Am. J. Physiol. Heart Circ. Physiol.
(2007) - et al.
Pressor and reflex sensitivity is altered in spontaneously hypertensive rats treated with angiotensin-(1-7)
Hypertension
(1995) - et al.
Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors
Clin. Sci. (Lond.)
(2011)
Role of angiotensin-(1-7) in the modulation of the baroreflex in renovascular hypertensive rats
Hypertension
Differential baroreceptor reflex modulation by centrally infused angiotensin peptides
Am. J. Physiol.
Metabolism of angiotensin-(1-7) by angiotensin-converting enzyme
Hypertension
Modulation of the baroreflex control of heart rate by angiotensin-(1-7) at the nucleus tractus solitarii of normotensive and spontaneously hypertensive rats
J. Hypertens.
Angiotensin-(1-7) and baroreflex function in nucleus tractus solitarii of (mRen2)27 transgenic rats
J. Cardiovasc. Pharmacol.
Hypotensive function of the brain angiotensin-(1-7) in Sprague Dawley and renin transgenic rats
J. Physiol. Pharmacol.
Brain-selective overexpression of human angiotensin-converting enzyme type 2 attenuates neurogenic hypertension
Circ. Res.
The angiotensin-(1-7)/Mas receptor axis is expressed in sinoatrial node cells of rats
J. Histochem. Cytochem.
Angiotensin-(1-7): cardioprotective effect in myocardial ischemia/reperfusion
Hypertension
Selective increase of angiotensin(1-7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training
Exp. Physiol.
Immunohistochemical localization of the angiotensin-(1-7) receptor Mas in the murine forebrain
Cell Tissue Res.
In vivo expression of angiotensin-(1-7) lowers blood pressure and improves baroreflex function in transgenic (mRen2)27 rats
J. Cardiovasc. Pharmacol.
Cited by (32)
Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic
2023, Biochemical PharmacologyCitation Excerpt :Apart from the local protective effects in the cardiovascular system, Ang (1–7) functions as an important neuromodulator, particularly in the hypothalamus, dorsomedial and ventral medulla, and areas involved in the tonic and reflex control of arterial pressure and heart rate [107–111]. In situ central Ang (1–7) infusion decreases blood pressure in transgenic hypertensive rats, DOCA salt-induced hypertensive rats, aldosterone/NaCl induced hypertensive rats, fructose-induced metabolic syndrome rats, two-kidney-one-clip (2K1C)-operated rats with renovascular hypertension, and stress-induced hypertensive rat [112–117]. The Ang (1–7)-MasR axis regulating blood pressure in the nervous system is linked to several central effects, such as elevated NOS activity, increased NO generation in the brain, enhanced release of arachidonic acid and vasopressin, decreased norepinephrine (NE) bioavailability, and suppression of oxidative stress.
The contribution of angiotensin peptides to cardiovascular neuroregulation in health and disease
2023, Angiotensin: From the Kidney to CoronavirusAnti-diarrheal therapeutic potential of diminazene aceturate stimulation of the ACE II/Ang-(1–7)/Mas receptor axis in mice: A trial study
2021, Biochemical PharmacologyCitation Excerpt :Other authors have demonstrated the ACE-II expression in normal intestinal mucosa and your dysregulation may cause gastrointestinal symptoms and injury [9-11]. In addition, Ang-(1–7) can still act as an AT1R antagonist [12–16]. These findings suggest that other potential pharmaceutical applications may be discovered for these molecules to treat intestinal disorders such as diarrhea [17–20].
Brain renin-angiotensin system in the pathophysiology of cardiovascular diseases
2017, Pharmacological ResearchCitation Excerpt :After chronic infusion, the expression of AngII and the AT1 receptor in the brain of SHR and DOCA-salt rats is significantly reduced [213,214] and the MAP is lowered; furthermore, the baroreflex control of arterial pressure and the cardiac autonomic tone are normalized in DOCA-salt rats [213] (see also Table 2). In support of this, an elevated AngII/Ang(1–7) ratio in the medulla of transgenic (mRen2)27 hypertensive rats [215] was shown to be connected by an impaired baroreflex function [216], and the icv infusion of Ang(1–7) in these hypertensive rats reduced BP, normalized baroreceptor control of HR, restored cardiac autonomic balance, reduced cardiac hypertrophy, and decreased imbalance of the AngII/Ang(1–7) ratio in the heart [217]. Interestingly, in Mas receptor knockout mice baroreceptor sensitivity is reduced [218].
Effect and mechanism of angiotensin (1-7) supplementation combined with exercise therapy on cardiac remodeling in rats with renal hypertension
2024, Chinese Journal of Tissue Engineering Research