Efeitos da ativação do eixo enzima conversora de angiotensina 2/angiotensina-(1-7)/receptor mas no metabolismo energético e na eletrofisiologia do coração
Several studies have reported many beneficial effects of the activation of the angiotensin-converting enzyme 2 (ACE2)/Angiotensin(Ang)-(1-7)/Mas receptor axis of the renin-angiotensin system in cardiovascular diseases. The aim of this study was to evaluate the effects of the activation of this axis...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2016 |
| Country: | Brasil |
| Institution: | Universidade Federal de Minas Gerais (UFMG) |
| Repository: | Repositório Institucional da UFMG |
| Language: | Portuguese |
| OAI Identifier: | oai:repositorio.ufmg.br:1843/35357 |
| Online Access: | http://hdl.handle.net/1843/35357 |
| Access Level: | Open access |
| Keyword: | Biologia celular Peptidil dipeptidase A Angiotensina II Receptores de angiotensina Coração |
| Summary: | Several studies have reported many beneficial effects of the activation of the angiotensin-converting enzyme 2 (ACE2)/Angiotensin(Ang)-(1-7)/Mas receptor axis of the renin-angiotensin system in cardiovascular diseases. The aim of this study was to evaluate the effects of the activation of this axis in the energetic metabolism and cardiac electrical physiology. Normal and hyperglycemic Wistar rats treated or not with the ACE2 activator diminazene aceturate (DIZE; 1 mg/kg diluted in saline; ~0.5 mL per animal, once a day by gavage for 30 days), [TGR (A1-7) 3292] transgenic rats and their controls (Sprague-Dawley rats), and Mas Knockout (Mas- KO) mice and their controls (C57BL6 mice) were used. Hyperglycemia was induced by streptozotocin (60 mg/kg/iv). After the treatment of normal rats, cardiac function parameters following ischemic/reperfusion (I/R), mitochondria function and electrophysiological profile of myocytes were assessed. DIZE treatment was able to protect the heart against I/R injuries and reperfusion arrhythmias, preserved the mitochondria function after ischemia and increased the ability of mitochondria in generating ATP, reducing proton leak without changing the specific citrate synthase activity. Moreover, the activation of the ACE2/Ang-(1-7)/Mas axis (treatment with DIZE and transgenic models) modulated the action potential (AP) parameters, shortening AP duration at 90%, reducing the sensibility of KATP to its agonist diazoxide and increasing the sensibility of KATP to its antagonist glybenclamide, resulting in an increase in the KATP density current. Treatment with DIZE did not change L-Type Ca2+ current. In hyperglycemic rats, the treatment with DIZE was not able to normalize neither hyperglycemia nor body weight loss. However, DIZE reversed hyperglycemia-induced cardiac electrical changes in the ventricular repolarization. Specifically, animals treated with DIZE showed a shorter QT and QTc intervals. In addition, DIZE was capable to short the AP duration at 90% in these animals, as well as to normalize the arrhythmic markers. ACE2 activation did not induce arrhythmic events in normal or hyperglycemic conditions. Thus, these results demonstrated a cardioprotective role of the activation of the ACE2/Ang-(1-7)/Mas axis by preserving mitochondrial function and modulating the cardiac electrical activity. |
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