Vascular Angiotensin-Converting Enzyme 2

Batlle, Daniel; Wysocki, Jan; Khan, Mirza S.

doi:10.1161/circresaha.110.229831

Cited by 6 publications

(7 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pivotal role of ACE2 as a negative regulator of Ang II-mediated signaling in the vascular system implies that ACE2 deficiency could facilitate the adverse effects of Ang II [15] , [16] , [17] , [24] , [28] . In the present study, aortic ACE2 protein is obviously reduced in WT mice in response to Ang II.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological inhibition of the Ang II signaling is a key aspect of the current approach to preventing vascular inflammation and oxidative stress-related vascular dysfunction [15] . Rencently, angiotensin-converting enzyme 2 (ACE2) has been identified as a pleiotropic monocarboxypeptidase responsible for the degradation of Ang II to the vasodilatory Ang-(1–7), which has been shown to counteract the pro-inflammatory and pro-oxidative effects of Ang II via its receptor Mas, thereby functioning as a negative regulator of the RAS [5] , [16] , [17] , [18] . Intriguingly, the Ang II type 1 (AT1) receptor blockers may increase expression and activity of ACE2 [9] , [19] with attenuation of cardiovascular oxidative damage [20] and diminish the profilin-1/ERK signaling [9] , [10] , [21] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ACE2 Deficiency Enhances Angiotensin II-Mediated Aortic Profilin-1 Expression, Inflammation and Peroxynitrite Production

et al. 2012

View full text Add to dashboard Cite

Inflammation and oxidative stress play a crucial role in angiotensin (Ang) II-mediated vascular injury. Angiotensin-converting enzyme 2 (ACE2) has recently been identified as a specific Ang II-degrading enzyme but its role in vascular biology remains elusive. We hypothesized that loss of ACE2 would facilitate Ang II-mediated vascular inflammation and peroxynitrite production. 10-week wildtype (WT, Ace2+/y) and ACE2 knockout (ACE2KO, Ace2−/y) mice received with mini-osmotic pumps with Ang II (1.5 mg.kg−1.d−1) or saline for 2 weeks. Aortic ACE2 protein was obviously reduced in WT mice in response to Ang II related to increases in profilin-1 protein and plasma levels of Ang II and Ang-(1–7). Loss of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, and IL-6 without affecting tumor necrosis factor-α in aortas of ACE2KO mice. Furthermore, ACE2 deficiency led to greater increases in Ang II-mediated profilin-1 expression, NADPH oxidase activity, and superoxide and peroxynitrite production in the aortas of ACE2KO mice associated with enhanced phosphorylated levels of Akt, p70S6 kinase, extracellular signal-regulated kinases (ERK1/2) and endothelial nitric oxide synthase (eNOS). Interestingly, daily treatment with AT1 receptor blocker irbesartan (50 mg/kg) significantly prevented Ang II-mediated aortic profilin-1 expression, inflammation, and peroxynitrite production in WT mice with enhanced ACE2 levels and the suppression of the Akt-ERK-eNOS signaling pathways. Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic inflammation and peroxynitrite production associated with the augmentation of profilin-1 expression and the activation of the Akt-ERK-eNOS signaling, suggesting potential therapeutic approaches by enhancing ACE2 action for patients with vascular diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ACE2 Deficiency Enhances Angiotensin II-Mediated Aortic Profilin-1 Expression, Inflammation and Peroxynitrite Production

et al. 2012

View full text Add to dashboard Cite

show abstract

“…It has been demonstrated that human ACE-2 enzyme is a negative regulator of RAAS [30,31], thus providing a crucial link between immunity, inflammation, increased coagulopathy, and cardiovascular disease, thereby serving as a protective mechanism against heart failure, myocardial infarction, lung disease, hypertension, vascular permeability, and diabetes [24,32] (Fig. 2).…”

mentioning

confidence: 99%

The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies

et al. 2020

View full text Add to dashboard Cite

SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the “cytokine storm” are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host’s cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.

show abstract

“…Clinical interventions targeting the RAS and its pathogenic actions have been centered on the use of RAS blockers [3]. More recently, it has been proposed that the RAS system could be therapeutically targeted by increasing Ang II degradation and Ang (1-7) formation via ACE2 enzyme activation [2,[4][5][6][7]. ACE2, a monocarboxypeptidase discovered in 2000, metabolizes Ang II by removing a single amino acid, phenylalanine, from the C-terminus of this peptide [8], which results in the formation of Ang-(1-7) [8,9].…”

mentioning

confidence: 99%

Reduced plasma ACE2 activity in dialysis patients: another piece in the conundrum of factors involved in hypertension and cardiovascular morbidity?

Wysocki

Batlle

2013

Nephrology Dialysis Transplantation

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) is a complex regulatory network consisting of enzymes and effector peptides that facilitate the maintenance of homeostasis of several physiological processes [1,2]. Upregulation of the RAS system, however, under chronic conditions and mainly through the interactions of Ang II with the AT1 receptor, can lead to hypertension and is involved in the progression of diabetic and nondiabetic chronic kidney disease (CKD) [2,3]. Clinical interventions targeting the RAS and its pathogenic actions have been centered on the use of RAS blockers [3]. More recently, it has been proposed that the RAS system could be therapeutically targeted by increasing Ang II degradation and Ang (1-7) formation via ACE2 enzyme activation [2,[4][5][6][7]. ACE2, a monocarboxypeptidase discovered in 2000, metabolizes Ang II by removing a single amino acid, phenylalanine, from the C-terminus of this peptide [8], which results in the formation of Ang-(1-7) [8,9]. Angiotensin-(1-7) has anti-inflammatory and antiproliferative actions that tend to counteract the proinflammatory and pro-proliferative effects of Ang II.ACE2 is a type-1 integral membrane glycoprotein [10] that is expressed largely in the kidney, and the intestine, but is also present in the heart, lungs and brain and is more ubiquitous than initially thought [2]. In its full-length form, ACE2 consists of three structural entities: the cytosolic, transmembrane and extracellular domains and has a molecular weight of 120-130 kD [11][12][13][14][15]. The extracellular domain of ACE2, which confers its enzymatic activity, contains a single catalytic metallopeptidase unit that shares 42% sequence identity and 61% sequence similarity with the catalytic domain of ACE [8]. Notably, pharmacologic ACE inhibitors used in clinical practice do not inhibit ACE2 [8].In this issue of Nephrology Dialysis Transplantation, Roberts et al. [16] showed that among patients with CKD plasma ACE2 activity is lower in those undergoing hemodialysis for end stage renal disease (ESRD) when compared with predialysis patients with CKD or renal transplant patients. When compared with historic samples from healthy subjects, however, all CKD groups examined, i.e. predialysis, transplant patients and even subjects on dialysis, seemed to have increased levels of plasma ACE2 activity. Statistical comparisons with healthy controls, however, could not be done because samples from healthy individuals were not assayed concurrently with those in the present study. What the study shows, in our opinion, is that while plasma ACE2 activity tends to increase in CKD patients, perhaps as a compensatory mechanism to attenuate Ang II overactivity, at the time that ESRD is reached and dialysis initiated a relative deficiency in plasma ACE2 activity ensues.What is then the significance of reduced plasma ACE2 activity in dialysis patients? As ACE2 is mainly involved with the degradation of Ang II, one could readily speculate that the levels of this peptide could be augmented thereby predisposing to hypertens...

show abstract

Vascular Angiotensin-Converting Enzyme 2

Cited by 6 publications

References 28 publications

ACE2 Deficiency Enhances Angiotensin II-Mediated Aortic Profilin-1 Expression, Inflammation and Peroxynitrite Production

ACE2 Deficiency Enhances Angiotensin II-Mediated Aortic Profilin-1 Expression, Inflammation and Peroxynitrite Production

The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies

Reduced plasma ACE2 activity in dialysis patients: another piece in the conundrum of factors involved in hypertension and cardiovascular morbidity?

Contact Info

Product

Resources

About