key: cord-333580-tw9cehxv
authors: Ferrario, Carlos M.
title: Commentary on “angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic”
date: 2020-07-24
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2020.07.041
sha: 
doc_id: 333580
cord_uid: tw9cehxv

nan

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 Figure 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, ACE, functioning as a dipeptidyl carboxypeptidase cleaves the proline (Pro 7 )-phenylalanine (Phe 8 ) bond of Ang II to liberate Ang-(1-7). 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 AT 1 -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] .

We appreciate the opportunity to clarify these issues without negating the interesting points raised by the authors of the above referred commentary. 

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic

Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensinconverting enzyme 2

Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats

Increased expression of angiotensin converting enzyme 2 in conjunction with reduction of neointima by angiotensin II type 1 receptor blockade

Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats

Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. Vasc Health Risk Manag

Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects

Cardiovascular actions of angiotensin(1-7)

The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin

The research studies reported in this Letter to the Editor from our laboratory have been conducted with grant HL-051952 from the National Heart and Lung Institute (NHLBI) of the National Institutes of Health (NIH).

The author declares no conflict of interest.