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Highlights: [•] Heart failure is increasing in prevalence associated with a huge economic burden. [•] ACE2 is a negative regulator of the renin–angiotensin system. [•] Elevated ACE2 activity is a biomarker in heart failure. [•] Enhancing ACE2 action may have unique therapeutic effects in patients with heart failure. [ABSTRACT FROM AUTHOR]

Abstract: Angiotensin converting enzyme (ACE) 2 is a key negative regulator of the renin–angiotensin system where it metabolizes angiotensin (Ang) II into Ang 1–7. We hypothesize that Ang II suppresses ACE2 by increasing TNF-α converting enzyme (TACE) activity and ACE2 cleavage. Ang II infusion (1.5mg/kg/day) in wild-type mice for 2weeks resulted in substantial decrease in myocardial ACE2 protein levels and activity with corresponding increase in plasma ACE2 activity, prevented by AT1R blockade. Ang II resulted in AT1R-mediated increase in myocardial TACE expression and activity, and membrane translocation of TACE. Ang II treatment in Huh7 cells exhibited AT1R-dependent metalloproteinase mediated shedding of ACE2 while transfection with siTACE prevented shedding of ACE2; cardiomyocyte-specific deletion of TACE also prevented shedding of ACE2. Reactive oxygen species played a key role since p47phoxKO mice were resistant to Ang II-induced TACE phosphorylation and activation with preservation of myocardial ACE2 which dampened Ang II-induced cardiac dysfunction and hypertrophy. In conclusion, Ang II induces ACE2 shedding by promoting TACE activity as a positive feedback mechanism whereby Ang II facilitates the loss of its negative regulator, ACE2. In HF, elevated plasma ACE2 activity likely represents loss of the protective effects of ACE2 in the heart. [Copyright &y& Elsevier]