Brain-Selective Overexpression of Human Angiotensin-Converting Enzyme Type 2 Attenuates Neurogenic Hypertension

Abstract

T he renin-angiotensin system (RAS) is well known for its physiological and pathophysiological roles in the regulation of blood pressure (BP) and cardiovascular function. 1,2 A new component of the RAS, angiotensin-converting enzyme (ACE) type 2 has been identified, from human heart failure ventricle and lymphoma cDNA libraries (reviewed elsewhere 3,4 ). Although the angiotensin-converting enzyme type 2 (ACE2) transcript was first described in heart, kidney and testis, additional studies reported ACE2 mRNA in rat medulla oblongata 4 and ACE2 activity in mouse brain. 5 Recently, we showed the presence of both ACE2 protein and mRNA widespread throughout the murine brain, in regions involved in the central regulation of cardiovascular function as well as noncardiovascular regions. 6 ACE2 converts Ang II into the vasodilatory peptide Ang-(1-7) with an affinity 400-fold higher than for Ang I. 7 In the central nervous system (CNS), Ang-(1-7) has been shown to enhance sensitivity of the bradycardic component of the cardiac baroreceptor reflex 8 and to promote vasodilation in hypertensive animals. 9,10 As a key enzyme in generating Ang-(1-7), ACE2 is thought to be a pivotal player in central BP regulation. 3,5 Several evidences from various laboratories have shown the beneficial effects of peripheral ACE2 in the regulation of cardiovascular hypertrophy and BP control. 10 -12 In the CNS, using a lentivirus coding for ACE2, Yamazato et al previously showed that ACE2 overexpression in the rostral ventrolateral medulla, could reverse hypertension in spontaneously hypertensive rats (SHR). 13 More recently, we reported that brain-targeted ACE2 overexpression in the subfornical organ (SFO) prevents the acute Ang II-mediated pressor and Original

Ontogeny of angiotensin-converting enzyme 2

“…Given that ACE2 mediates antihypertrophic effects in cardiomyocytes (15), it is conceivable that progressively increasing cardiac ACE2 activity during gestation may regulate growth of the myocardium. Central overexpression of ACE2 downregulates AT 1 R expression in the brain, attenuates hypertension, and improves arterial baroreflex induced by Ang II infusion or in spontaneously hypertensive rats (13). Collectively, these findings indicate a critical role for ACE2 in the central regulation of blood pressure and the development of hypertension.…”

“…Genetic inactivation of angiotensinogen, renin, ACE, or AT1R in mice causes abnormal glomerular and renal vascular development, pelvic dilation (hydronephrosis), and hypoplastic papilla (10). Accumulating evidence indicates that ACE2 plays an important role in the regulation of cardiac structure and function (11), age-related glomerulosclerosis (12), central regulation of blood pressure (13), and acute lung injury (14). To our knowledge, the expression and the role of ACE2 during kidney, lung, heart, and brain development is largely unknown.…”

ACE2–angiotensin-(1–7)–Mas axis and oxidative stress in cardiovascular disease

“…92 In addition, ACE2 overexpression in the brain prevented the Ang II-mediated decrease in NOS expression in regions involved in blood pressure regulation. 93 Zhang et al 94 reported that the central administration of Ang-(1-7) stimulates NO release and upregulates eNOS in a rat model of cerebral ischemia/reperfusion, further corroborating the antioxidant actions of ACE2 in the brain.…”

Role of Brain Angiotensin (1-7) In Chronic Hyperglycaemia Induced Nephropathy in Wistar Rats

“…Rats were infused ICV with artificial cerebrospinal fluid (ACSF; in mmol/l) 147 NaCl, 2.9 KCl, 1.6 MgCl 2 , 1.7 CaCl 2 , and 2.2 dextrose) 35 for two weeks. In the same way, the ICV administration of valsartan (100 nmol/day, 2 weeks) 36 and angiotensin (1-7) (4.8 µmol/day, 2 weeks) 37 in single or in combination were given in volume of 5µl (ACSF) in both lateral ventricles by using a Hamilton microsyringe. Hamilton microsyringe positioned in the injection cannula and the syringe was kept in place for 2 minutes in order to allow for the diffusion of the injected volume and prevents pressure-induced damage.…”