Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Abstract Introduction Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Brain angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. Purpose We hypothesized that orally administered firibastat (previously named RB150), an orally central acting APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Methods Two days after MI induced by the left anterior descending artery ligation, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI+vehicle), firibastat (150 mg/kg; MI+firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI+enalapril) as a positive control. Results From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment during four weeks after MI normalized brain APA hyperactivity, with a return to the control values measured in the sham group. Four and six weeks after MI, MI+firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI+vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI+firibastat mice displayed lower levels of mRNA for markers of fibrosis such Ctgf and collagen types I and III than MI+vehicle mice. Conclusions Chronic oral firibastat administration after MI in mice normalizes brain APA hyperactivity, thereby normalizing brain RAS hyperactivity, whilst preventing cardiac dysfunction and attenuating cardiac hypertrophy and fibrosis. Acknowledgement/Funding INSERM, College de France, ANR LabCom, and Quantum Genomics

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Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

AJP Renal Physiology ◽

10.1152/ajprenal.00050.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. F398-F407 ◽

Cited By ~ 63

Author(s):

Juan Carlos Q. Velez ◽

Alison M. Bland ◽

John M. Arthur ◽

John R. Raymond ◽

Michael G. Janech

Keyword(s):

Mesangial Cells ◽

Renin Angiotensin System ◽

Ang Ii ◽

Glomerular Injury ◽

Renin Substrate ◽

Angiotensin System ◽

Renin Angiotensin ◽

Neprilysin Inhibitor ◽

Aminopeptidase A ◽

Aminopeptidase A Inhibitor

Intraglomerular ANG II has been linked to glomerular injury. However, little is known about the contribution of podocytes (POD) to intraglomerular ANG II homeostasis. The aim of the present study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for peptide determination from conditioned cell media and customized AQUA peptides for quantification. Immortalized mouse POD were incubated with 1-2 μM ANG I, ANG II, or the renin substrate ANG-(1-14) for different time intervals and coincubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. POD incubated with 1 μM ANG I primarily formed ANG-(1-9) and ANG-(1-7). In contrast, MES incubated with ANG I primarily generated ANG II. In POD, ANG-(1-7) was the predominant product, and its formation was inhibited by a neprilysin inhibitor. Modest angiotensin-converting enzyme (ACE) activity was also detected in POD, although only after cells were incubated with 2 μM ANG I. In addition, we observed that POD degraded ANG II into ANG III and ANG-(1-7). An aminopeptidase A inhibitor inhibited ANG III formation, and an ACE2 inhibitor led to ANG II accumulation. Furthermore, we found that POD converted ANG-(1-14) to ANG I and ANG-(1-7). This conversion was inhibited by a renin inhibitor. These findings demonstrate that POD express a functional intrinsic renin-angiotensin system characterized by neprilysin, aminopeptidase A, ACE2, and renin activities, which predominantly lead to ANG-(1-7) and ANG-(1-9) formation, as well as ANG II degradation. These findings may reflect a specific role of POD in maintenance of intraglomerular renin-angiotensin system balance.

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