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Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats
Piratello, Aline Cristina;Moraes-Silva, Ivana;Paulini, Janaina;Souza, Pamella Ramona;Sirvente, Raquel;Salemi, Vera;Flues, Karin;Moreira, Edson Dias;Mostarda, Cristiano;Cunha, Tatiana;Casarini, Dulce Elena;Irigoyen, Maria Claudia;
Clinics , 2010, DOI: 10.1590/S1807-59322010001200019
Abstract: objective: the aim of this study was to evaluate the role of angiotensin i, ii and 1-7 on left ventricular hypertrophy of wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. methods: ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. results: hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). blood pressure variability was higher in denervated groups than in their respective controls. left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with wistar controls. both hypertensive groups presented a higher concentration of angiotensin ii than wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the wistar groups. there was no difference in angiotensin i concentration among groups. conclusion: our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin ii and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. these data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.
Adenoviral Delivery of Angiotensin-(1-7) or Angiotensin-(1-9) Inhibits Cardiomyocyte Hypertrophy via the Mas or Angiotensin Type 2 Receptor  [PDF]
Monica Flores-Mu?oz, Bruno M. D. C. Godinho, Abdulaziz Almalik, Stuart A. Nicklin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045564
Abstract: The counter-regulatory axis of the renin angiotensin system peptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a potential therapeutic target in cardiac remodelling, acting via the mas receptor. Furthermore, we recently reported that an alternative peptide, Ang-(1-9) also counteracts cardiac remodelling via the angiotensin type 2 receptor (AT2R). Here, we have engineered adenoviral vectors expressing fusion proteins which release Ang-(1-7) [RAdAng-(1-7)] or Ang-(1-9) [RAdAng-(1-9)] and compared their effects on cardiomyocyte hypertrophy in rat H9c2 cardiomyocytes or primary adult rabbit cardiomyocytes, stimulated with angiotensin II, isoproterenol or arg-vasopressin. RAdAng-(1-7) and RAdAng-(1-9) efficiently transduced cardiomyocytes, expressed fusion proteins and secreted peptides, as demonstrated by western immunoblotting and conditioned media assays. Furthermore, secreted Ang-(1-7) and Ang-(1-9) inhibited cardiomyocyte hypertrophy (Control = 168.7±8.4 μm; AngII = 232.1±10.7 μm; AngII+RAdAng-(1-7) = 186±9.1 μm, RAdAng-(1-9) = 180.5±9 μm; P<0.05) and these effects were selectively reversed by inhibitors of their cognate receptors, the mas antagonist A779 for RAdAng-(1-7) and the AT2R antagonist PD123,319 for RAdAng-(1-9). Thus gene transfer of Ang-(1-7) and Ang-(1-9) produces receptor-specific effects equivalent to those observed with addition of exogenous peptides. These data highlight that Ang-(1-7) and Ang-(1-9) can be expressed via gene transfer and inhibit cardiomyocyte hypertrophy via their respective receptors. This supports applications for this approach for sustained peptide delivery to study molecular effects and potential gene therapeutic actions.
DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy  [PDF]
Ruben Martín, Maria Miana, Raquel Jurado-López, Ernesto Martínez-Martínez, Nieves Gómez-Hurtado, Carmen Delgado, Maria Visitación Bartolomé, José Alberto San Román, Claudia Cordova, Vicente Lahera, Maria Luisa Nieto, Victoria Cachofeiro
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041545
Abstract: Background The natural triterpenes, erythrodiol and uvaol, exert anti-inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied. Methodology/Principal Findings The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-γ, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals. Conclusions/Significance Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac myofibroblasts. They inhibit the angiotensin II-induced proliferation in a PPAR-γ-dependent manner, while at high doses they activate pathways of programmed cell death that are dependent on JNK and PPAR-γ.
Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II  [PDF]
Walid Mokni,Thérèse Keravis,Nelly Etienne-Selloum,Alison Walter,Modou O. Kane,Valérie B. Schini-Kerth,Claire Lugnier
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014227
Abstract: Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored.
Role of Angiotensin-(1-7) on Renal Hypertrophy in Streptozotocin-Induced Diabetes Mellitus  [PDF]
Dante Amato, Alma R. Nú?ez-Ortiz, José del Carmen Benítez-Flores, David Segura-Cobos, Pedro López-Sánchez, Beatriz Vázquez-Cruz
Pharmacology & Pharmacy (PP) , 2016, DOI: 10.4236/pp.2016.79046
Participation of angiotensin II in chronic kidney diseases including diabetic nephropathy (DN) has been extensively described. Similarly, several studies support a protective role for angiotensin-(1-7). However, other studies suggest that some of the cellular effects of angiotensin-(1-7) may be deleterious. The objective of this study was to determine the role of exogenous angiotensin-(1-7) on renal hypertrophy development in rats with streptozotocin-induced diabetes. A control group and three groups of rats with streptozotocin-induced diabetes: untreated diabetic rats, diabetic rats treated with captopril, and diabetic rats treated with angiotensin-(1-7), were studied. After two weeks of treatment, the kidneys were removed under anesthesia with pentobarbital. The kidneys were weighed and the renal cortex was separated for analysis of AT1R, TGF-β1, MASR, and ACE2 expression by western blot. Rats in the three groups with diabetes had hyperglycemia, increased food and water consumption, and higher urinary volume than control rats. Treatment with captopril or angiotensin-(1-7) reversed streptozotocin-induced renal hypertrophy, measured by kidney weight, protein/DNA ratio in renal cortex, glomerular area, or proximal tubular cells area, proteinuria, and creatinine clearance reduction. AT1R, TGF-β1, and MAS receptor expression in renal cortex of diabetic rats increased significantly as compared to controls (p < 0.05); treatment with captopril or angiotensin-(1-7) reversed such increments. ACE2 in the renal cortex decreased in diabetic rats, but it was increased after treatment with captopril or angiotensin-(1-7). These findings suggest that exogenous administration of angiotensin-(1-7) may be renoprotective in early stages of diabetes mellitus.
Angiotensin-Converting Enzyme 2 Over-Expression in the Central Nervous System Reduces Angiotensin-II-Mediated Cardiac Hypertrophy  [PDF]
Yumei Feng, Chetan Hans, Elizabeth McIlwain, Kurt J. Varner, Eric Lazartigues
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048910
Abstract: Angiotensin-converting enzyme type 2 (ACE2) has been shown to be an important member of the renin angiotensin system. Previously, we observed that central ACE2 reduces the development of hypertension following chronic angiotensin II (Ang-II) infusion in syn-hACE2 transgenic (SA) mice, in which the human ACE2 transgene is selectively targeted to neurons. To study the physiological consequences of central ACE2 over-expression on cardiac function and cardiac hypertrophy, SA and non-transgenic (NT) mice were infused with Ang-II (600 ng/kg/min, sc) for 14 days, and cardiac function was assessed by echocardiography. Blood pressure (BP), hemodynamic parameters, left ventricle (LV) mass/tibia length, relative ventricle wall thickness (2PW/LVD), cardiomyocyte diameters and collagen deposition were similar (P>0.05) between NT and SA mice during saline infusion. After a 2-week infusion, BP was elevated in NT but not in SA mice. Although ejection fraction and fractional shortening were not altered, Ang-II infusion increased 2PW/LVD compared to saline infusion in NT mice. Interestingly, the 2PW/LVD and LV mass/tibia ratios were significantly lower in SA compared to NT mice at the end of infusion. Moreover, Ang-II infusion significantly increased arterial collagen deposition and cardiomyocytes diameter in NT mice but not in transgenic animals (P<0.05). More importantly, ACE2 over expression significantly reduced the Ang-II-mediated increase in urine norepinephrine levels in SA compared to NT mice. The protective effect of ACE2 appears to involve reductions in Ang-II-mediated hypertension and sympathetic nerve activity.
Angiotensin II receptor blockers and cardiovascular protection: Focus on left ventricular hypertrophy regression and atrial fibrillation prevention  [cached]
Cesare Cuspidi,Francesca Negri,Alberto Zanchetti
Vascular Health and Risk Management , 2008,
Abstract: Cesare Cuspidi1,2, Francesca Negri2, Alberto Zanchetti31Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, Italy; 2Policlinico di Monza; 3Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Università di Milano, and Istituto Auxologico Italiano, Milan, ItalyAbstract: Left ventricular hypertrophy (LVH) and atrial fibrillation (AF) are strong predictors of cardiovascular (CV) morbidity and mortality, independently of blood pressure levels and other modifiable and nonmodifiable risk factors. The actions of circulating and tissue angiotensin II, mediated by AT1 receptors, play an important role in the development of a wide spectrum of cardiovascular alterations, including LVH, atrial enlargement and AF. Growing experimental and clinical evidence suggests that antihypertensive drugs may exert different effects on LVH regression and new onset AF in the setting of arterial hypertension. Since a number of large and adequately designed studies have found angiotensin II receptor blockers (ARBs) to be more effective in reducing LVH than beta-blockers and data are also available showing their effectiveness in preventing new or recurrent AF, it is reasonable to consider this class of drugs among first line therapies in patients with hypertension and LVH (a very high risk phenotype predisposing to AF) and as adjunctive therapy to antiarrhythmic agents in patients undergoing pharmacological or electrical cardioversion of AF.Keywords: angiotensin II receptor blockers, left ventricular hypertrophy, atrial fibrillation
Mice lacking the Cβ subunit of PKA are resistant to angiotensin II-induced cardiac hypertrophy and dysfunction
Linda C Enns, Kenneth L Bible, Mary J Emond, Warren C Ladiges
BMC Research Notes , 2010, DOI: 10.1186/1756-0500-3-307
Abstract: Angiotensin II (ang II) induced hypertension in both PKA Cβ null mice and their WT littermates. However, PKA Cβ null mice were resistant to a number of ang II-induced, cardiopathological effects observed in the WT mice, including hypertrophy, decreased diastolic performance, and enlarged left atria.The Cβ subunit of PKA plays an important role in angiotensin-induced cardiac dysfunction. The Cβ null mouse highlights the potential of the PKA Cβ subunit as a pharmaceutical target for hypertrophic cardiac disease.PKA is a ubiquitous cellular kinase that is involved in regulating a vast number of different cellular processes. Several studies have implicated altered PKA signaling in cardiomyopathy [1,2]. For example, the onset of cardiac hypertrophy is influenced by alterations in muscle-specific A-kinase Anchoring Protein (mAKAP) signaling in myocytes. AKAPs subcellularly localize and modulate interactions between PKA and its downstream targets [3]. Deficiencies in the PKA pathway have also been linked both to cardiomyopathy in humans due to reduced phosphorylation of downstream targets such as cardiac troponin I [4], and to preservation of cardiac function against pressure overload in mice [5,6].PKA is a tetrameric protein, consisting of two regulatory subunits and two catalytic subunits. Binding of cAMP to the regulatory subunits releases the catalytic subunits, which are then free to interact with and phosphorylate downstream targets. There are four isoforms of the regulatory subunit (RIα, RIβ, RIIα, RIIβ) and three types of catalytic subunits (Cα, Cβ, Cγ) [7,8]. C57/BL6J male mice lacking the regulatory RIIβ subunit have been found to be resistant to a number of age-related pathologies, including cardiac hypertrophy and decline [9]. We are currently studying mice lacking the PKA catalytic C? subunit to establish whether they also enjoy age-delaying benefits. To date, we know that when challenged with a high fat, high calorie diet, these mice show robust obesity resis
柚皮素减轻AngⅡ诱导的原代大鼠心肌细胞肥大作用 Naringenin Alleviates Angiotensin Ⅱ Induced Neonatal Rat Ventricular Cardiomyocytes Hypertrophy  [PDF]
- , 2017,
Abstract: 目的:探讨柚皮素(Naringenin)对血管紧张素Ⅱ(AngⅡ)诱导的原代大鼠心肌细胞(NRVMs)肥大作用及其作用机制。方法:AngⅡ刺激NRVMs构建体外心肌肥大模型,分为Vehicle组、Naringenin组、AngⅡ组和AngⅡ+Naringenin组。CCK8检测心肌细胞活性,α-actinin免疫荧光染色检测心肌细胞横截面积,RT-PCR检测ANP、BNP mRNA表达水平,Western Blot检测JNK、ERK及P38蛋白磷酸化水平,Hoechst染色检测心肌细胞凋亡。结果:与对照组相比,AngⅡ组心肌细胞横截面积明显增大,ANP、BNP mRNA表达水平明显增加,给予柚皮素干预后心肌细胞面积减小,ANP、BNP mRNA表达水平降低;此外,柚皮素能够减轻AngⅡ诱导的ERK和P38蛋白磷酸化水平上调及心肌细胞凋亡。结论:柚皮素可以减轻AngⅡ刺激引起的心肌细胞肥大,其机制可能与抑制MAPK信号通路以及减轻心肌细胞凋亡有关
Inhibition of Angiotensin II-Induced Cardiac Hypertrophy and Associated Ventricular Arrhythmias by a p21 Activated Kinase 1 Bioactive Peptide  [PDF]
Rui Wang, Yanwen Wang, Wee K. Lin, Yanmin Zhang, Wei Liu, Kai Huang, Derek A. Terrar, R. John Solaro, Xin Wang, Yunbo Ke, Ming Lei
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101974
Abstract: Cardiac hypertrophy increases the risk of morbidity and mortality of cardiovascular disease and thus inhibiting such hypertrophy is beneficial. In the present study, we explored the effect of a bioactive peptide (PAP) on angiotensin II (Ang II)-induced hypertrophy and associated ventricular arrhythmias in in vitro and in vivo models. PAP enhances p21 activated kinase 1 (Pak1) activity by increasing the level of phosphorylated Pak1 in cultured neonatal rat ventricular myocytes (NRVMs). Such PAP-induced Pak1 activation is associated with a significant reduction of Ang II-induced hypertrophy in NRVMs and C57BL/6 mice, in vitro and in vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Thus our results suggest that Pak1 activation achieved by specific bioactive peptide represents a potential novel therapeutic strategy for cardiac hypertrophy and associated ventricular arrhythmias.
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