We read with interest the well-balanced Comment by Zheng and colleagues (COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 17, 259–260; 2020)1 and their Reply (Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19’. Nat. Rev. Cardiol. 17, 313–314; 2020)2 to the Correspondence written by Mourad and Levy (Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat. Rev. Cardiol. 17, 313; 2020)3.
We have reported the capacity of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) to increase the left ventricular levels of Ace2 mRNA when given to normotensive rats either under normal conditions4 or following coronary artery ligation5. This work revealed the existence of a negative feedback mechanism in which the angiotensin-converting enzyme 2 (ACE2)–angiotensin-(1–7)–Mas receptor axis counterbalances the pathological effects of angiotensin II6. In their Reply2, Zheng and colleagues suggest that the mechanism underlying the increase in levels of cardiac Ace2 mRNA and ACE2 activity by these drugs was undetermined; we wish to clarify that we did elucidate the mechanism by which these medications augment the expression of ACE2 (refs7,8,9).
In these studies, the inhibitory effect of angiotensin II on the transcription of Ace2 in cultured cerebellar or medullary astrocytes from rats was prevented by exposure to losartan or valsartan but not PD123319 (a blocker of angiotensin II receptor type 2)7. A similar finding was obtained in cultured cardiomyocytes and cardiac fibroblasts from neonatal rats8; in these in vitro experiments, the inhibitory effect of angiotensin II on the transcription of Ace2 and on ACE2 enzymatic activity was replicated by the treatment of cardiomyocytes with exogenous endothelin 1 (ref.8). The inhibitory effect of angiotensin II on Ace2 transcription is mediated by activation of extracellular signal-regulated kinase 1 (ERK1; also known as MAPK3) and ERK2 (also known as MAPK1)8,9. In addition, treatment of rat neonatal cardiomyocytes in vitro with atrial natriuretic peptide reversed the downregulation of Ace2 transcription induced by angiotensin II or endothelin 1 (ref.8). We have also shown that angiotensin II reduces Ace2 transcription and ACE2 activity in rat aortic smooth muscle cells in vitro via activation of a MAPK phosphatase pathway9, as confirmed by others10.
These experiments show that Ace2 expression in cardiac tissues in rats depends on the balance and concentration of regulatory molecules. We appreciate the opportunity to highlight the cellular signalling mechanisms by which ARBs increase Ace2 expression and ACE2 activity, especially given that ACE inhibitors and ARBs have opposite effects on the plasma and tissue concentrations of angiotensin II and angiotensin-(1–7) (ref.6).
Zheng, Y.-Y., Ma, Y.-T., Zhang, J.-Y. & Xie, X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 17, 259–260 (2020).
Zheng, Y.-Y., Ma, Y.-T., Zhang, J.-Y. & Xie, X. Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19’. Nat. Rev. Cardiol. 17, 313–314 (2020).
Mourad, J.-J. & Levy, B. I. Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat. Rev. Cardiol. 17, 313 (2020).
Ferrario, C. M. et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 111, 2605–2610 (2005).
Ishiyama, Y. et al. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 43, 970–976 (2004).
Ferrario, C. M., Ahmad, S., Joyner, J. & Varagic, J. Advances in the renin angiotensin system focus on angiotensin-converting enzyme 2 and angiotensin-(1–7). Adv. Pharmacol. 59, 197–233 (2010).
Gallagher, P. E., Chappell, M. C., Ferrario, C. M. & Tallant, E. A. Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am. J. Physiol. Cell Physiol. 290, C420–C426 (2006).
Gallagher, P. E., Ferrario, C. M. & Tallant, E. A. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am. J. Physiol. Heart Circ. Physiol. 295, H2373–H2379 (2008).
Gallagher, P. E., Ferrario, C. M. & Tallant, E. A. MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides. Am. J. Physiol. Cell Physiol. 295, C1169–C1174 (2008).
Koka, V. et al. Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am. J. Pathol. 172, 1174–1183 (2008).
The work by the authors described in this Correspondence was carried out with support from the National Heart, Lung, and Blood Institute of the NIH (grant HL-051952).
The authors declare no competing interests.
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Ferrario, C.M., Ahmad, S. & Groban, L. Mechanisms by which angiotensin-receptor blockers increase ACE2 levels. Nat Rev Cardiol 17, 378 (2020). https://doi.org/10.1038/s41569-020-0387-7
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