Dear Sir
I wish to clarify the accuracy of certain conclusions advanced in a recently published commentary by Cure and Cure [1]. In their interesting article which outlines concerns regarding the potential adverse evolution of SARS-CoV-2 infection in diabetic patients medicated with blockers of the renin angiotensin system (RAS), it is incorrectly stated that angiotensin converting enzyme 2 (ACE2; EC 3.4.17.23) hydrolyzes angiotensin-(1–9) [Ang-(1–9)] into angiotensin-(1–7) [Ang-(1–7)]. Despite a 42% sequence similarity with its homologue angiotensin converting enzyme (ACE; EC 3.4.15.1), ACE2 functions as a mono-carboxypeptidase cleaving one single amino acid sequentially at the C-terminal amino acid from susceptibles substrates [2]. As shown in Fig. 1 , ACE2 cleaves the penultimate amino acid in angiotensin I (Ang I) to generate Ang-(1–9). The nonapeptide is then processed into Ang-(1–7) by ACE. In contrast, ACE2, functioning as a mono-carboxypeptidase cleaves the proline (Pro7)-phenylalanine (Phe8) bond of Ang II to liberate Ang-(1–7) from Ang II. The second point that needs correction is the suggestion that angiotensin receptor blockers (ARBs) cause a reduction in Ang II levels (plasma, tissue?) in part by upregulation of Ace2 gene transcription and increased enzymatic activity [3]. While original studies from my laboratory first documented increased cardiac [3,4] and vascular [5,6] ACE2 mRNA and ACE2 activity in response to administration of ARBs, the effect was associated with increased, not decreased, plasma Ang II. The increase in Ang II in response to ARB administration is the result of blockade of AT1-R and consequent prevention of the uptake of the peptide into the cell. Multiple studies have confirmed Ang-(1–7) antihypertensive and reno protective actions in adults treated with RAS inhibitors [7,8] since we first reported Ang-(1–7) vasodilator response in the areflexic rat [9]. Lastly, a similar robust literature has documented that Ang-(1–7) leads to peripheral sympathetic nerve activity tone-down via its actions in the central nervous system [10].
Fig. 1.
Diagram of angiotensins sequential metabolism from the shorter form of angiotensin-(1–12) substrate which is cleaved from the hepatic substrate angiotensinogen by kallikrein or kallikrein like enzyme.
We appreciate the opportunity to clarify these issues without negating the interesting points raised by the authors of the above referred commentary.
Funding source
The research studies reported in this Letter to the Editor from our laboratory have been conducted with grant HL-051952 from the United States of America (USA) National Heart and Lung Institute (NHLBI) of the USA National Institutes of Health (NIH) .
Declaration of competing interest
The author declares no conflict of interest.
References
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