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ace2

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Official Full Name
angiotensin I converting enzyme 2
Background
The protein encoded by this gene belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. This secreted protein catalyzes the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7. The organ- and cell-specific expression of this gene suggests that it may play a role in the regulation of cardiovascular and renal function, as well as fertility. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronaviruses SARS and HCoV-NL63. [provided by RefSeq, Jul 2008]
Synonyms
ACE2; angiotensin I converting enzyme 2; ACEH; angiotensin-converting enzyme 2; peptidyl-dipeptidase A; metalloprotease MPROT15; ACE-related carboxypeptidase; angiotensin-converting enzyme homolog; angiotensin I converting enzyme (peptidyl-dipeptidase A) 2; zgc:92514

Angiotensin-converting enzyme 2 (ACE2) is a member of the renin-angiotensin system (RAS). It is a pleiotropic monocarboxypeptidase with high homology to ACE, but ACE2 has the opposite effect of ACE. The ACE2 gene is located on chromosome Xp22 (5) and contains 18 exons. ACE2 is a zinc ion-dependent metalloprote consisting of 805 amino acids. ACE2 is consistent with the distribution of ACE, and it plays a role in the negative regulation of RAS system in vivo. Most tissues in the ACE distribution have a distribution of ACE2, such as heart, kidney, testis, placenta, colon, and small intestine. However, compared with ACE, ACE2 mRNA expression is not as extensive as ACE. It has high tissue specificity, mainly distributed in coronary artery, renal vascular endothelium, and renal tubular endothelium.

ACE2 has only one enzyme active site that acts between the proline (Pro) and hydrophobic amino acids of the substrate. It can hydrolyze the C-terminal leucine residue of AngI to produce angiotensin (1~9) [Ang(1~9)]. Ang (1~9) can be transformed into the active polypeptide angiotensin (1~7) [Ang(1~7)] under the action of ACE. ACE2 can also hydrolyze AngII to produce Ang (1~7), and the activity is more than 400 times that of hydrolyzed Ang I. This suggests that the main physiological role of ACE2 is to decompose AngII. Ang (1~7), a cardiovascular protective peptide with diastolic blood vessels, diuretic, diuretic, anti-growth and anti-proliferative effects, is considered to be one of the most potent vasoactive substances against Ang II. The above suggests that ACE2 may be a negative antagonist of RAS. After hydrolysis of AngI and AngII by ACE2, the content of angiotensin peptides with vasoconstriction effect is reduced, the level of vasodilator substances in the body is increased, and Ang (1~7) is produced to exert vasodilator effect. Therefore, the most direct result of ACE2 hydrolysis of angiotensin family members is the relaxation of blood vessels, causing blood pressure to drop. ACE2 may act as a transregulation of ACE and play a role in vasomotor regulation. In addition, in the RAS metabolic pathway, the ACE2-Ang(1-7)-Mas axis plays an antagonistic role with the ACE-AngII-AT1 (AngII1-type receptor) axis. This provides a new target for the research and treatment of the pathogenesis of many organ tissues such as heart, kidney, liver, and intestine.

Figure 1.The counter-regulatory role of ACE2/Ang-(1–7)/MasR axis activation on AngII/AT1R-induced progression of diabetic cardiomyopathy. (Patel, et al. 2014).

ACE2 is an extremely critical regulator of cardiac function. ACE2 knockout mice have severe cardiac dysfunction, mainly characterized by thinning of the left ventricle and decreased systolic function. This reveals that the ACE2-Ang(1-7)-Mas axis plays a role in the physiological processes of the heart. Studies have shown that overexpression of ACE2 can also regulate the imbalance of MMPs/TIMPs system and reduce the expression of the fibrosis index of transforming growth factor-β (TGF-β) and its marker α smooth muscle actin (smooth muscle actin-α, α-SMA). At the same time, it will also reduce AngII, increase the expression of Ang (1-7), make the RAS system balance to the protective direction, and improve myocardial hypertrophy and myocardial remodeling. Therefore, ACE2 is achieved by converting AngII to Ang (1-7), and Ang (1-7) directly acts on fibroblasts of the myocardium to achieve myocardial remodeling by balancing MMPs/TIMPs.

As a key enzyme in the RAS system, ACE2 is highly expressed in various parts of the kidney. In the human renal tubules, glomerular visceral epithelial cells and parietal epithelial cells, vascular smooth muscle cells, interlobular artery endothelial cells have ACE2 distribution, and actively participate in the physiological and pathological processes of the kidney. In the kidney of ACE2 gene-deficient rats, AngII increased significantly. As a result, fibrous collagen deposition increased and glomerular sclerosis occurred early. The kidneys of the mice were excised for 4 weeks while an angiotensin receptor blocker (ARB) drug was used as a control. Renal injury and proteinuria were exacerbated by the use of the ACE2 inhibitor LMN-4760 alone or in combination with ARB without changing blood pressure. This reveals that ACE2 has a protective effect on early chronic kidney disease.

As a key enzyme in the RAS system, ACE2 is highly expressed in various parts of the kidney. In the human renal tubules, glomerular visceral epithelial cells and parietal epithelial cells, vascular smooth muscle cells, interlobular artery endothelial cells have ACE2 distribution, and actively participate in the physiological and pathological processes of the kidney. In the kidney of ACE2 gene-deficient rats, AngII increased significantly. As a result, fibrous collagen deposition increased and glomerular sclerosis occurred early. The kidneys of the mice were excised for 4 weeks while an angiotensin receptor blocker (ARB) drug was used as a control. Renal injury and proteinuria were exacerbated by the use of the ACE2 inhibitor LMN-4760 alone or in combination with ARB without changing blood pressure. This reveals that ACE2 has a protective effect on early chronic kidney disease.

Studies have shown that RAS imbalance is one of the main reasons for the formation of liver fibrosis, and activation of ACE2-Ang(1-7)-Mas axis can prevent liver damage. During the formation of liver fibrosis, the expression of ACE2 and Ang(1-7) was significantly correlated with liver function index and liver fibrosis, and both showed negative regulation. The ACE2-Ang(1-7)-Mas axis is also actively involved in the metabolic process of the liver. Ang (1-7) is closely related to the function of glucose metabolism in the liver, which can inhibit the gluconeogenesis of the liver.

Silva et al. found that Mas and apolipoprotein E (ApoE) double knockout mice showed more severe fatty liver, and more expression level of dyslipidemia and serum alanine aminotransferase compared to wild-type or single-knockout mice. Therefore, the Mas receptor may be involved in the fat metabolism of the liver, and its activation has a potential protective function against hepatic steatosis in mice. In addition, the expression of ACE and TLR4 in the liver decreased, and the expression of ACE2 and NF-κB increased. These results were related to the decreased expression of IL-6 and TNF-α, and the inflammatory state of liver tissue was greatly improved. Feltenberger et al. found that oral administration of Ang (1-7) to high-fat-fed mice improved liver metabolism and reduced liver inflammation and liver fat deposition. Meanwhile, it still reduced plasma total cholesterol, triglyceride, and alanine aminotransferase levels. It is speculated that Ang (1-7) can prevent liver fat deposition in obese mice and play a positive role in preventing and treating fatty liver. These findings suggest that ACE2 plays an important role in liver damage and liver metabolism.

ACE2 is involved in the process of intestinal amino acid transport, which is combined with the neutral amino acid transporter BOAT1 to participate in the absorption process of amino acids in the intestine. Promoting ACE2 expression increases the activity of the neutral amino acid carrier in the intestinal mucosa, increasing the transport of neutral amino acids. If the ACE2 gene is knocked out, B0AT1 is not affected in the mRNA level of the small intestine, but protein expression completely disappears. This demonstrates that BOAT1 relies on the tissue-specific protein ACE2 in the small intestine to function. ACE2 also plays a vital role in the steady state maintenance of the intestine. Liu C et al. knocked out the mouse ACE2 gene by RNA transfection technology and successfully obtained an animal model of colitis. These ACE2 knockout mice exhibited clinical signs of colonic shortening, diarrhea, weight loss, leukocyte infiltration, and intestinal mucosal damage. In summary, ACE2 is involved in intestinal amino acid metabolism, regulates intestinal microecological balance, and is closely related to intestinal inflammation.

Reference:

  1. Fang F, Liu G C, Zhou X, et al. Loss of ACE2 exacerbates murine renal ischemia-reperfusion injury. Plos One, 2013, 8(8):e71433.
  2. Zhang W, Miao J, Li P, et al. Up-regulation of components of the renin-angiotensin system in liver fibrosis in the rat induced by CCL₄. Research in Veterinary Science, 2013, 95(1):54-58.
  3. Silva A R, Aguilar E C, Alvarezleite J I, et al. Mas receptor deficiency is associated with worsening of lipid profile and severe hepatic steatosis in ApoE-knockout mice. Am J Physiol Regul Integr Comp Physiol, 2013, 305(11):R1323-R1330.
  4. Santos S H, Andrade J M, Fernandes L R, et al. Oral Angiotensin-(1-7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet. Peptides, 2013, 46:47-52.
  5. Feltenberger J D, Andrade J M, Paraã­So A, et al. Oral formulation of angiotensin-(1-7) improves lipid metabolism and prevents high-fat diet-induced hepatic steatosis and inflammation in mice. Hypertension, 2013, 62(2):324-330.
  6. Liu C, Xiao L, Li F, et al. Generation of outbred Ace2 knockout mice by RNA transfection of TALENs displaying colitis reminiscent pathophysiology and inflammation. Transgenic Research, 2015, 24(3):433-446.
  7. Patel V B, Parajuli N, Oudit G Y. Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clinical Science, 2014, 126(7):471-82.