Angiotensin Convreting Enzyme

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ACE may be considered the activation step in the catalytic cascade for the formation of Ang II from Ang I (Fig. 1). Although evidence of non-ACE pathways for biosynthesis of Ang II is evident (Sadjadi et al 2005a; Tokuyama et al 2002), ACE likely represents the major, if not sole enzyme responsible for Ang II formation under normal physiological conditions in humans and other species. This is not to imply that ACE has no other substrates than Ang I (see below), but that a primary role for ACE is the generation of Ang II. Indeed, the identification of ACE and the characterization of the enzymatic properties must be considered a pivotal achievement in our understanding of the RAAS and cardiovascular disease, as well as leading to the successful development of ACE inhibitors in the treatment for hypertension and renal disease. ACE is a metallopeptidase composed of a single monomeric protein. Somatic ACE contains two catalytic regions designated as the amino (N) and carboxy (C) domains. Selective inhibitors against both catalytic domains of somatic ACE are now available, however, the functional significance of the two domains is presently unknown (Dive et al 1999; Georgiadis et al 2003). The enzyme cleaves two residues from the carboxy end of various peptides and, hence, its description as a dipeptidyl-carboxypepitdase. Within the kidney, somatic ACE is primarily a glycosylphosphatidylinositol-anchored membrane protein and the majority of the enzyme including both catalytic regions faces the extracellular space. ACE is localized throughout the kidney with high concentrations in vascular endothelial cells, proximal tubules and interstitial cells. ACE is also released from the apical surface of epithelial cells into the proximal tubular fluid and likely contributes to the urinary levels of the enzyme (Hattori et al 2000). Indeed, the tubular fluid should be considered a distinct intrarenal compartment that contains RAAS processing enzymes and the peptide products may interact with Ang receptors along the entire tubular area of the kidney. The release of ACE from the cell membrane is a specific process as releasing enzymes or "sheddases" have been identified that recognize a unique motif on the stalk region of the enzyme (Beldent et al 1993). The conversion of membrane-bound ACE to a soluble form does not appear to substantially alter the substrate preference or the catalytic properties of the enzyme. Although the significance of this event is not currently understood, enzyme shedding may underlie an endocrine process to transport ACE to more distal areas of the nephron that are deficient in this peptidase activity for the discrete production of Ang II. In this regard, Casarini and colleagues have presented intriguing data that the urinary excretion of the N-terminal domain of ACE may serve as a urinary marker in both humans and experimental hypertensive models (Marques et al 2003).

Extensive evidence suggests that intrarenal ACE participates in the direct formation of Ang II from Ang I. The renal administration of ACE inhibitors reduces interstitial levels of Ang II and attenuates blood pressure. Moreover, in an animal model of tissue-depleted ACE that preserves circulating levels of the enzyme, renal Ang II is significantly reduced (Modrall et al 2003). Interestingly, intrarenal levels of Ang I were also markedly reduced in the tissue ACE null mouse while renal Ang-(1-7) concentrations were maintained (Modrall et al 2003). These data serve to emphasize that ACE participates in the metabolism of other peptide hormones (Skidgel & Erdos 2004). In the case of Ang-(1-7), ACE efficiently metabolizes the peptide to Ang-(1-5), a product which is presently not known to exhibit functional activity (Chappell et al 1998; Deddish et al 1998; Rice et al 2004). We have postulated that the formation of Ang-(1-7), particularly under prolonged activation of the RAAS, is considered to balance or attenuate the constrictor and prolifer-ative actions of Ang II (Chappell & Ferrario 1999; Ferrario et al 2005c). Indeed, Ang-(1-7) exhibits vasodilatory, natriuretic and anti-proliferative actions through the stimulation of nitric oxide and arachidonic acid metabolites (Sampaio et al 2007). Ang-(1-7) abrogates the Ang II-dependent activation of MAP kinase in primary cultures of proximal tubule epithelial cells (Su et al 2006). Moreover, the inhibitory actions of Ang-(1-7) were blocked by the Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7) suggesting a receptor mediated pathway distinct from either AT! or AT2 receptor subtypes (Su et al 2006). Similar effects of Ang-(1-7) were originally demonstrated in non-renal cells (Tallant et al 2005a). In the circulation, ACE inhibitors increase circulating levels of Ang-(1-7) and augment the in vivo half life of the peptide by almost 6 fold (Iyer et al 1998; Yamada et al 1998). The urinary excretion of Ang-(1-7) increases in both human and experimental hypertensive models following acute administration of ACE inhibitors (Ferrario et al 1998; Yamada et al 1999). The increased excretion of Ang-(1-7) most likely reflects the reduced intrarenal metabolism of the peptide and the efficient shunting of the Ang I pathway to formation of Ang-(1-7). Our recent studies in isolated sheep proximal tubules reveal that without prior inhibition of ACE, Ang-(1-7) derived from either Ang I or Ang II was rapidly converted to Ang-(1-5) (Shaltout et al 2007). Blockade of Ang-(1-7) partially reverses the beneficial actions of ACE inhibitors on blood pressure in hypertensive rats as an Ang-(1-7) monoclonal antibody or the [D-Ala7]-Ang-(1-7) antagonist increase blood pressure (Iyer et al 1997; Iyer et al 2000). Moreover, studies by Benter and colleagues find that the renoprotective effects of exogenous Ang-(1-7) in LNAME-treated SHR were not further improved with the ACE inhibitor captopril (Benter et al 2006a).

Apart from Ang II and Ang-(1-7), renal ACE may also participate in the metabolism of other peptides including kinins, substance P and the hematopoietic fragment acetyl-Ser-Asp-Lys-Pro (Ac-SDKP). Bradykinin-(1-9) is very rapidly metabolized by ACE in a two -step process to the inactive fragments bradykinin-(1-7) and bradykinin-(1-5). ACE inhibition is associated with increased circulating and tissue levels of bradykinin-(1-9) and the renal content of kinin is higher in the tissue ACE null mouse (Campbell et al 2004). In general, bradykinin is a potent vasodilator and inhibitor of cell growth through stimulation of nitric oxide, as well as exhibiting natriuretic actions within the kidney (Scicli & Carretero 1986). Interestingly, Santos and colleagues have reported that the functional activity of Ang-(1-7), under certain conditions, is dependent on the increased release of bradykinin (Fernandes et al 2001). Moreover, the kinin B2 receptor antagonist H0E140 blocked nitric oxide release by the non-peptide Ang-(1-7) agonist AVE0991 (Wiemer et al 2002).

Similar to Ang-(1-7), circulating levels of the Ac-SDKP are markedly increased with ACE inhibition and the enzyme cleaves the Lys-Pro bond of the tetrapeptide (Azizi et al 1997; Raousseau et al 1995). Although current evidence does not support a role for Ac-SDKP in the regulation of blood pressure, the peptide does exhibit potent anti-fibrotic and anti-inflammatory actions (Peng et al 2003). Indeed, exogenous administration of Ac-SDKP attenuates proteinuria and improves renal function in several models of renal injury and hypertension (Omata et al 2006). Interestingly, Ang-(1-7) and Ac-SDKP may be the only known endogenous substrates that are exclusively cleaved by the N-terminal catalytic domain of human ACE (Raousseau et al 1995; Deddish et al 1998). Moreover, prolyl (oligo)endopeptidase, an enzyme that processes Ang I or Ang II to Ang-(1-7) in endothelial and neural cells (Chappell et al 1990; Santos et al 1992), may also convert thymosin-^ to Ac-SDKP in plasma and tissue (Cavasin et al 2004). The unusual specificity of the N-domain of ACE for Ang-(1-7) and Ac-SDKP suggests an overlap of the activities of these two peptide systems within the kidney as well. Although elucidation of the signaling mechanisms and receptors for Ang-(1-7) and Ac-SDKP is at an early stage, future studies should consider whether there is a basis for the functional similarities between these peptides.

The role of RAAS enzymes including ACE and renin has been primarily emphasized for their catalytic properties; however, compelling evidence now reveals receptor-like properties for these two enzymes. Indeed, a renin receptor was recently cloned by Nyguen and colleagues with significant concentrations of the protein in the glomerulus and vascular smooth muscle cells. (Diez-Freire et al 2006; Nguyen et al 2002). Receptor-bound renin exhibits increase proteolyitc activity for Ang I formation, but both pro-renin and renin also induce distinct signaling pathways following binding. In isolated mesangial cells, exogenous renin increased TGF-P expression and other matrix proteins including plasminogen activator inhibitor (PAI-1) and fibronectin that was apparently independent of Ang II synthesis (Huang et al 2006). ACE inhibitors may also induce cell-specific signaling by inducing conformational changes in membrane-bound ACE without alterations in Ang II or other peptides (Benzing et al 1999). Two kinases, c-Jun kinase and MAP kinase kinase 7 associate with the intracellular portion of ACE. Moreover, ACE inhibitors increase the phosphorylation and nuclear trafficking of phosphorylated cJun kinase (Kohlstedt et al 2002). This aspect of ACE-dependent activation of various kinases has been demonstrated in human endothelial cells and the question remains as to what extent this occurs in other cells or tissues. In addition, ACE inhibitors or the angiotensin peptides Ang-(1-9) and Ang-(1-7) induce the association of ACE and the bradykinin B2 receptor that prevents the rapid down-regulation of the ligand-receptor complex, thus potentiating the actions of bradykinin (Burckle et al 2006; Chen et al 2005).

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