Maintenance of Normal Blood Pressure and Renal Functions Are Independent Effects of Angiotensin-converting Enzyme

Kessler, Sean P.; Senanayake, P.; Scheidemantel, Thomas S.; Gomos, Janette B.; Rowe, T.; Sen, Ganes C.

doi:10.1074/jbc.m302347200

Cited by 25 publications

(52 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, despite wild type levels of soluble sACE and angiotensin II in the serum of both groups, only the mice expressing sACE in the vascular endothelial cells had normal blood pressure. These results demonstrate that secreted ACE alone is insufficient for maintaining blood pressure; expression of endothelial cell-associated ACE was critical (29). In direct contrast, another study also using genetically altered mice showed that serum sACE levels alone, in the absence of endothelial cell-associated sACE, maintained normal blood pressure (30).…”

Section: Discussionmentioning

confidence: 87%

“…However, whether the angiotensin II generated in the serum (by soluble sACE) and that generated in the endothelial tissue (by endothelial cell-associated sACE) are equally efficient in maintaining blood pressure is still controversial. Utilizing the transgenic technology, the role of ACE, either as a cell-associated or as a soluble molecule is now being determined (29,30). This is accomplished by expressing just one type of ACE in the target tissue of AceϪ/Ϫ mice (29).…”

Section: Discussionmentioning

confidence: 99%

“…Utilizing the transgenic technology, the role of ACE, either as a cell-associated or as a soluble molecule is now being determined (29,30). This is accomplished by expressing just one type of ACE in the target tissue of AceϪ/Ϫ mice (29). In two such transgenic lines, sACE is expressed either in vascular endothelial cells or in renal proximal tubules.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Tyrosine Phosphorylation in the Regulation of Cleavage Secretion of Angiotensin-converting Enzyme

Santhamma¹,

Sadhukhan²,

Kinter

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Both germinal (gACE) and somatic (sACE) isozymes of angiotensin-converting enzyme (ACE) are type I ectoproteins whose enzymatically active ectodomains are cleaved and shed by a membrane-bound protease. Here, we report a role of protein tyrosine phosphorylation in regulating this process. Strong enhancements of ACE cleavage secretion was observed upon enhancing protein Tyr phosphorylation by treating gACE-or sACEexpressing cells with pervanadate, an inhibitor of protein Tyr phosphatases. Secreted gACE, cell-bound mature gACE and its precursors were all Tyr-phosphorylated, as was the endoplasmic reticulum protein, immunoglobulin heavy chain-binding protein, that co-immunoprecipitated with ACE. The enhancement of cleavage secretion by pervanadate did not require the presence of the cytoplasmic domain of ACE, and it was not accomplished by enhancing the rate of intracellular processing of the protein. The observed enhancement of cleavage secretion of ACE in pervanadate-treated cells was specifically blocked by an inhibitor of the p38 mitogen-activated protein (MAP) kinase but not by inhibitors of many other Ser/Thr and Tyr protein kinases, including a specific inhibitor of protein kinase C that, however, could block the enhancement of cleavage secretion elicited by phorbol ester. These results indicate that ACE Tyr phosphorylation, probably in the endoplasmic reticulum, enhances the rate of its cleavage secretion at the plasma membrane using a regulatory pathway that may involve p38 MAP kinase.Renin-angiotensin system is considered a major regulator of fluid homeostasis, electrolyte balance and blood pressure. Angiotensin-converting enzyme (ACE), 1 a key component of this system, converts the inactive precursor angiotensin I to the active pressor hormone angiotensin II (1). It also inactivates bradykinin, a vasodilator. The role of ACE within the reninangiotensin system is well established, and inhibition of this enzyme is routinely used for therapeutic management of hypertension. ACE-like proteins have been identified in lower organisms, such as Drosophila (2, 3), indicating that it is an evolutionarily conserved protein that also shows an overall sequence homology of 80 -90% across mammalian species. This evolutionary importance of ACE, coupled with its widespread distribution in many organs within a species, suggests that over and above its role in the renin-angiotensin system, ACE probably plays a much broader role in general physiology. This notion is supported by the severely abnormal phenotype of ACE knockout mouse (4 -6).There are two different isozymic forms of ACE. These are derived from the same gene by tissue specific choice of alternative transcription initiation sites. The larger somatic ACE (sACE), a component of the renin-angiotensin system, is expressed in vascular endothelial cells, renal proximal tubule epithelial (RTE) cells, intestinal brush border cells, macrophages, and monocytes. The smaller germinal ACE (gACE) is expressed exclusively in the maturing sperm and is involved in male reproductio...

show abstract

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Tyrosine Phosphorylation in the Regulation of Cleavage Secretion of Angiotensin-converting Enzyme

Santhamma¹,

Sadhukhan²,

Kinter

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…ACE plays a central role in blood pressure regulation. Transgenic studies have shown that secreted ACE alone could not maintain a normal blood pressure; expression of ACE in vascular endothelial cells is absolutely necessary (20). A suitable balance between the levels of ACE on the cell surface and in the serum is critical for maintaining a normal blood pressure.…”

Section: Discussionmentioning

confidence: 99%

“…Germinal ACE, the smaller isoform (116 kDa), is expressed only in maturing sperm cells and is involved in male fertility. Studies on tissue-specific expression of ACE revealed that expression of sACE in vascular endothelial tissue is essential for maintaining normal blood pressure (20). Both the isoforms of ACE are expressed on the cell surface as a type I ectoprotein, with a short cytoplasmic domain, a transmembrane domain, and a long extracellular domain containing the active site(s), and are cleaved on the membrane proximal region to release the enzymatically active extracellular domain in the body fluid, including serum (21)(22)(23).…”

mentioning

confidence: 99%

Calmodulin Binds to the Cytoplasmic Domain of Angiotensin-converting Enzyme and Regulates Its Phosphorylation and Cleavage Secretion

Chattopadhyay

Santhamma

Sengupta

et al. 2005

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The rate of cleavage secretion of the enzymatically active ectodomain of angiotensin-converting enzyme (ACE) is regulated by tyrosine phosphorylation of the protein and by the phorbol ester, phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. Here, we report that both calmodulin inhibitor (CaMI) and calmodulin kinase inhibitor could also enhance cleavage secretion of ACE. This effect was accompanied by the dissociation of calmodulin from a specific region within the cytoplasmic domain of ACE to which it had been bound. The same domain of ACE was phosphorylated, and both CaMI and PMA caused dephosphorylation of ACE as well. Mass spectrometric and mutational analyses identified Ser 730 as the only phosphorylated residue in the cytoplasmic domain of ACE. The Ser 730 3 Ala mutant of ACE was not phosphorylated, but it still bound calmodulin, and its cleavage secretion was enhanced by both CaMI and PMA. Similarly, when Ser 730 was replaced by the phosphoserine mimetic, Asp, cleavage secretion of the resultant mutant remained susceptible to the enhancing effect of CaMI and PMA. These results demonstrate that, although CaMI and PMA can enhance both cleavage secretion of ACE and its dephosphorylation, the two effects are not mutually interdependent.Numerous integral membrane proteins can release their biologically active ectodomain from the cell surface to the extracellular milieu by a regulated proteolytic event called "ectodomain shedding" (1-3). Ectodomain shedding plays a vital role in various cellular functions, including cell growth (4), mammalian development (5), and disease (4, 6). The group of proteins that undergo ectodomain shedding includes growth factors, receptors, cell adhesion molecules, ectoenzymes such as angiotensin-converting enzyme (ACE), 3 and others, e.g. ␤-amyloid precursor protein (7,8). The proteases responsible for ectodomain shedding, the "sheddases," are also a member of transmembrane protein family (7). Some of the proteolytic events are carried out by ADAM (a disintegrin and metalloproteinase) family of proteases (9). Tumor necrosis factor-␣-converting enzyme (TACE, also known as ADAM 17), was the first secretase with known physiological substrate (tumor necrosis factor-␣) to be isolated and characterized (10,11). TACE is also involved in shedding of a number of transmembrane proteins, including L-selectin (12), ␤-amyloid precursor protein (13), epidermal growth factor receptor ligands (14, 15), and growth factor receptors (16 -18).ACE (also known as kininase II and CD143) is a central component of the renin-angiotensin system, which regulates blood pressure, electrolyte balance, and fluid homeostasis. ACE participates in blood pressure regulation by converting inactive decapeptide angiotensin I to vasoactive octapeptide angiotensin II and by inactivating the vasodilator bradykinin. ACE exists as two isoforms, namely somatic ACE (sACE) and germinal ACE (gACE), which are generated from the same gene with tissue-specific choice of transcription from two alternative promot...

show abstract

Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders

Magill

2014

Comprehensive Physiology

View full text Add to dashboard Cite

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hypertension will also be reviewed in this article.

show abstract

Maintenance of Normal Blood Pressure and Renal Functions Are Independent Effects of Angiotensin-converting Enzyme

Cited by 25 publications

References 42 publications

Role of Tyrosine Phosphorylation in the Regulation of Cleavage Secretion of Angiotensin-converting Enzyme

Role of Tyrosine Phosphorylation in the Regulation of Cleavage Secretion of Angiotensin-converting Enzyme

Calmodulin Binds to the Cytoplasmic Domain of Angiotensin-converting Enzyme and Regulates Its Phosphorylation and Cleavage Secretion

Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders

Contact Info

Product

Resources

About