Abstract-Rat models of hypertension, eg, spontaneously hypertensive stroke-prone rats (SHRSP), display reduced angiotensin-converting enzyme 2 (ACE2) mRNA and protein expression compared with control animals. The aim of this study was to investigate the role of ACE2 in the pathogenesis of hypertension in these models. Therefore, we generated transgenic rats on a SHRSP genetic background expressing the human ACE2 in vascular smooth muscle cells by the use of the SM22 promoter, called SHRSP-ACE2. In these transgenic rats vascular smooth muscle expression of human ACE2 was confirmed by RNase protection, real-time RT-PCR, and ACE2 activity assays. Transgene expression leads to significantly increased circulating levels of angiotensin-(1-7), a prominent product of ACE2. Mean arterial blood pressure was reduced in SHRSP-ACE2 compared to SHRSP rats, and the vasoconstrictive response to intraarterial administration of angiotensin II was attenuated. The latter effect was abolished by previous administration of an ACE2 inhibitor. To evaluate the endothelial function in vivo, endothelium-dependent and endothelium-independent agents such as acetylcholine and sodium nitroprusside, respectively, were applied to the descending thoracic aorta and blood pressure was monitored. Endothelial function turned out to be significantly improved in SHRSP-ACE2 rats compared to SHRSP. These data demonstrate that vascular ACE2 overexpression in SHRSP reduces hypertension probably by locally degrading angiotensin II and improving endothelial function. Thus, activation of the ACE2/angiotensin-(1-7) axis may be a novel therapeutic strategy in hypertension. (Hypertension. 2008;52:967-973.)
BACKGROUND AND PURPOSEAVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation. EXPERIMENTAL APPROACHWe used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse −1 , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg −1 ·per day, s.c.) or saline (100 μL·kg −1 ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates. KEY RESULTSTreatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs. CONCLUSIONS AND IMPLICATIONSAVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.
Diminished release and function of endothelium-derived nitric oxide (NO) coupled with increases in reactive oxygen species (ROS) production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)] and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic ACE2 would improve endothelial function by decreasing the ROS production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule ACE2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1mg/kg/day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7) and it was reduced in Mas knockout mice. These effects were associated with reduction in ROS production. In addition, Ang II-induced ROS production in human aortic endothelial cells was attenuated by pre-incubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that ACE2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.
It has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1-7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1-7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1-7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1-7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1-7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1-7)/Mas axis is essential for normal ORM processing.
The renin-angiotensin system (RAS) is related to physiological adaptations induced by exercise. Angiotensin-converting enzyme (ACE) 2 is a major regulator of the RAS in tissues, as it metabolizes angiotensin (Ang) II to Ang-(1-7). The aim of this study was to determine the effects of ACE2 deficiency on physical performance and physiological adaptations induced by voluntary running. Physical performance, body composition and plasma angiotensin levels, as well as tissue morphology and gene expression of RAS components in the left ventricle (LV) and skeletal muscle (gastrocnemius), were evaluated in ACE2-deficient (ACE2(-/y)) and wild-type (ACE2(+/y)) mice after 6 weeks of voluntary wheel running. ACE2(-/y) mice run less than ACE2(+/y) mice (19±4.7 vs. 26±12.6 revolutions per day × 100, P<0.01). The ACE2(+/y) group presented a lower fat mass (15±1.1%) and higher muscle mass (76.6±1.6%) after 6 weeks of voluntary running compared with the sedentary control group (fat mass: 18.3±2.1%; muscle mass: 72.7±2.2). However, no change in body composition was observed in ACE2(-/y) mice after exercise. Heart and skeletal muscle hypertrophy was observed only in trained ACE2(+/y) mice. Besides a small decrease in Ang I in ACE2(-/y) mice, plasma levels of angiotensin peptides remained unchanged by exercise or ACE2 deficiency. In the LV of trained animals, AT2 gene expression was higher in ACE2(+/y) compared with ACE2(-/y) mice. ACE2 deficiency leads to an increase in AT1 gene expression in skeletal muscle. ACE expression in soleus was increased in all exercised groups. ACE2 deficiency affects physical performance and impairs cardiac and skeletal muscle adaptations to exercise.
Research supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG). The authors have nothing to disclose.
Several evidences have shown that salt excess is an important determinant of cardiovascular and renal derangement in hypertension. The present study aimed to investigate the renal effects of chronic high or low salt intake in the context of hypertension and to elucidate the molecular mechanisms underlying such effects. To this end, newly weaned male SHR were fed with diets only differing in NaCl content: normal salt (NS: 0.3%), low salt (LS: 0.03%), and high salt diet (HS: 3%) until 7 months of age. Analysis of renal function, morphology, and evaluation of the expression of the main molecular components involved in the renal handling of albumin, including podocyte slit-diaphragm proteins and proximal tubule endocytic receptors were performed. The relationship between diets and the balance of the renal angiotensin-converting enzyme (ACE) and ACE2 enzymes was also examined. HS produced glomerular hypertrophy and decreased ACE2 and nephrin expressions, loss of morphological integrity of the podocyte processes, and increased proteinuria, characterized by loss of albumin and high molecular weight proteins. Conversely, severe hypertension was attenuated and renal dysfunction was prevented by LS since proteinuria was much lower than in the NS SHRs. This was associated with a decrease in kidney ACE/ACE2 protein and activity ratio and increased cubilin renal expression. Taken together, these results suggest that LS attenuates hypertension progression in SHRs and preserves renal function. The mechanisms partially explaining these findings include modulation of the intrarenal ACE/ACE2 balance and the increased cubilin expression. Importantly, HS worsens hypertensive kidney injury and decreases the expression nephrin, a key component of the slit diaphragm.
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