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.
Highlights
The renin angiotensin system (RAS) plays an essential role in the physiological and pathological regulation of cardiovascular function and cardiac remodeling both at the periphery and in the central nervous system (CNS) [1]
Angiotensin-converting enzyme type 2 (ACE2) gene expression was first identified in various tissues such as kidney, heart, lung, and testis, it appears that its expression is ubiquitous, including in the CNS and throughout brain regions involved in central regulation of cardiovascular function [4,5]
angiotensin II (Ang-II) infusion significantly decreased the left ventricle internal diameter (LVID) and left ventricle volume (LV Vol) in NT and syn-hACE2 transgenic (SA) compared to saline infusion (P,0.05)
Summary
The renin angiotensin system (RAS) plays an essential role in the physiological and pathological regulation of cardiovascular function and cardiac remodeling both at the periphery and in the central nervous system (CNS) [1]. Several groups have shown that peripheral ACE2 has beneficial effects in the regulation of cardiac hypertrophy through degradation of Ang-II [8,9,10]. The role of central ACE2 in the regulation of cardiac function and hypertrophy has not been addressed. In this study, using a transgenic mouse model over-expressing human ACE2 in the CNS, we investigated the role of central ACE2 in Ang-II-induced cardiac hypertrophy. Our data suggest that chronic ACE2 over-expression in the brain decreased Ang-IImediated cardiac hypertrophy and collagen deposition, reduced urinary norepinephrine levels and partially protected SA transgenic mice from sympathetic -mediated cardiac hypertrophy and fibrosis
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