Key result
Ex vivo recombinant ACE2 normalizes elevated Ang II and restores Ang 1-7 in acute HF.
Why the study?
Although RAS is activated in HF and ACE2 and Ang-(1-7) are negative regulators of RAS, angiotensin peptide levels and the effects of rhACE2 on peptide metabolism in human HF plasma and tissue needed comprehensive evaluation.
Cohort (n=126)
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Now we've not only got an entire fingerprint of how a good pathway is defective and how the bad pathway is activated in heart failure patients, we've shown how recombinant human ACE2 restores the balance very effectively with little or no side effects.”
“This research is a terrific example of how the university works together synergistically to develop world-class research and translate that into medicines that impact patient outcomes.”
Review demonstrates the cardioprotective potential of recombinant human ACE2 in heart failure, highlighting therapeutic regulation of angiotensin peptide pathways.
BACKGROUND: The renin-angiotensin system (RAS) is activated in heart failure (HF) and inhibition of RAS is a mainstay therapy for HF. Angiotensin-converting enzyme 2 (ACE2) and its product, angiotensin 1-7 (Ang-[1-7]), are important negative regulators of the RAS. OBJECTIVES: A comprehensive examination of angiotensin peptide levels and therapeutic effects of recombinant human ACE2 (rhACE2) on peptide metabolism was evaluated in human plasma and explanted heart tissue from patients with HF. METHODS: Using prospective cohorts with chronic (n = 59) and acute (n = 42) HF, plasma angiotensin analysis was performed using a unique liquid chromatography-mass spectrometry/mass spectroscopy method quantifying circulating and equilibrium levels. Angiotensin II (Ang II) metabolism was examined in human explanted hearts with dilated cardiomyopathy (n = 25). RESULTS: The dynamic range of the RAS was large, with equilibrium angiotensin levels being 8- to 10-fold higher compared with circulating angiotensin levels. In chronic HF patients receiving ACE inhibition, plasma Ang II was suppressed and plasma Ang-(1-7) was elevated, whereas acute HF and patients receiving angiotensin receptor blocker had higher plasma Ang II with lower Ang-(1-7) levels. Suppressed Ang-(1-7)/Ang II ratio was associated with worsening HF symptoms and longer hospitalization. Recombinant human ACE2 effectively metabolized Ang-(1-10) and Ang II into Ang-(1-9) and Ang-(1-7), respectively. Myocardial Ang II levels in explanted human hearts with dilated cardiomyopathy were elevated despite ACE inhibition with elevated chymase activity, and Ang II was effectively converted to Ang-(1-7) by rhACE2. CONCLUSIONS: Plasma angiotensin peptides represent a dynamic network that is altered in HF and in response to rhACE2. An increased plasma Ang-(1-7) level is linked to ACE inhibitor use, whereas acute HF reduced Ang-(1-7) levels and suppressed the Ang-(1-7)/Ang II ratio. Increased chymase activity elevated Ang II levels in failing human hearts. Use of rhACE2 effectively normalized elevated Ang II while increasing Ang-(1-7) and Ang-(1-9) levels.
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Basu et al. (2017) conducted a cohort in Heart failure (n=126). Recombinant human ACE2 (rhACE2) and ACE inhibitors/ARBs was evaluated on Plasma angiotensin peptide levels and metabolism. In patients with heart failure, acute HF reduced Ang-(1-7) levels, while ex vivo use of recombinant human ACE2 effectively normalized elevated Ang II and increased Ang-(1-7) levels.
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