Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration

Alvarenga, Erika Costa de; Fonseca, Matheus de Castro; Carvalho, Clarissa Coelho de; Florentino, Rodrigo M.; França, Andressa; Matias, Eveline; Guimarães, Paola Bianchi; Batista, Carolina; Freire, V. N.; Carmona, Adriana K.; Pesquero, João Bosco; Paula, Ana; Foureaux, Giselle; Leite, Maria de Fátima

doi:10.1371/journal.pone.0165371

Cited by 29 publications

(28 citation statements)

References 75 publications

(101 reference statements)

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“…10C), which is consistent with observations obtained for neuronal stem cells [46], vascular smooth muscle cells [47], cardiac fibroblasts [48] or murine melanoma cells, where ATII increases proliferation by binding to the receptor ACE [42]. In murine melanoma cells, proliferation is triggered by an increase of intracellular Ca 2+ [42], which is in accordance with our observation that ATII increases Ca 2+ in MV3 cells (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…We conclude that not only the ATII-stimulated NHE1 activity, but also an interplay of various effects, including ATII-triggered increase of MMP activity, and possibly ATII-mediated activation of angiotensin converting enzyme (ACE) may play a significant role in promoting adhesion and invasion. ACE usually converts ATI to ATII at the surface of endothelial cells, and its activity can be stimulated by its reaction product, ATII [42]. ATII/ACE interaction has been shown to be involved in phospholipase C/Ca 2+ signaling [42].…”

Section: Discussionmentioning

confidence: 99%

“…ACE usually converts ATI to ATII at the surface of endothelial cells, and its activity can be stimulated by its reaction product, ATII [42]. ATII/ACE interaction has been shown to be involved in phospholipase C/Ca 2+ signaling [42]. …”

Section: Discussionmentioning

confidence: 99%

“…At this point, an interplay between the receptors ACE, AT 1 and AT 2 needs to be taken into consideration. In the presence of ATII at a critical concentration, the effect of losartan may be the result not only of the blockade of AT 1 , but also of an additional, synchronous stimulation of AT 2 [57] and ACE [42]. While the long-term effect of AT 2 signaling known to suppress AT 1 expression [58], cannot account for the decreased NHE1 activity after a 30-40 min incubation with ATII and losartan, the AT 2 -mediated short-term effects leading to intracellular acidification [59] may be caused by an AT 2 -induced decrease in NHE1 activity.…”

Section: Discussionmentioning

confidence: 99%

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The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Hofschröer

Nielsen

et al. 2018

Cell Physiol Biochem

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Background/Aims: The peptide hormone angiotensin II (ATII) plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT₁), the stimulation of which induces an increase in cytosolic [Ca²⁺] and calmodulin activation. Ca²⁺-bound (activated) calmodulin stimulates the activity of the Na⁺/ H⁺ exchanger isoform 1 (NHE1); and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT₁ receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT₁ mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3) cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca²⁺] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT₁ and the angiotensin II receptor type 2 (AT₂). Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca²⁺/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT₁ was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT₂ inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT₁ antagonists (sartans) in hypertensive cancer patients should therefore be given critical consideration.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Hofschröer

Nielsen

et al. 2018

Cell Physiol Biochem

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“…Е. С. Alvarenga и соавт. объясняют механизм пролиферации и миграции клеточной линии меланомы ТМ-15 более выраженной активацией ангиотензина 2 (АТ2) при связывании с ангиотензинпревращающим ферментом (АПФ), чем с его классическим рецептором АТ2 типа 1 (ATR1), и запуском ядерного сигнала Ca 2+ транслокацией комплекса АТ2 / АПФ в ядро с индукцией патологических изменений [10].…”

Section: Introductionunclassified

Tissue synthesis of some components of the renin-angiotensin system in hypertensive patients with localized kidney cancer

et al. 2020

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Background. In the last decade, the relationship between arterial hypertension and the risk of developing kidney cancer (KC) has been pointed out. Some studies have shown that the metabolic imbalance of the components of the renal renin-angiotensin system (RAS) is associated with the development and progression of KC.Objective: to study the state of RAS in tumor and peritumoral tissues in patients with KC on the background of arterial hypertension. Materials and methods. In patients with localized KC T1N0M0 and grade I–II arterial hypertension without special treatment (n = 40) in the samples of tumor, peritumoral and histologically unchanged tissue, the levels of angiotensins 1, 2, 1–7 (AT1, AT2, AT(1–7)) of angiotensin-converting enzymes (ACE, ACE2) were determined by ELISA. The comparison group consisted of patients with RC without impaired blood pressure (n = 55).Results. In patients with KC, the level of AT1 is 1.5 times higher (p <0.05), and AT2 is 1.6 times higher (p <0.05) in tumor tissue against the background of unchanged content in peritumoral tissue compared with histologically unchanged tissue. The level of ACE is higher than histologically unchanged tissue by 2.7 times, ACE2 – by 1.6 times (in all cases p <0.05), and in peritumoral tissue it is identical in histologically unchanged tissue.In patients with KC and arterial hypertension, the level of AT1 and AT2 in the tumor tissue is 1.8 times higher (p <0.05) and 2.1 times (p <0.01), respectively, the content of AT(1–7) is 1.6 times (p <0.01). In peritumoral tissue, AT1 is 1.6 times higher (p <0.01) and AT2 is 1.9 times higher (p <0.05). The level of AT(1–7) in the peritumoral tissue is identical to the values in the histologically unchanged tissue. The content of ACE and ACE2 in tumor tissue is 3.6 and 2.9 times higher, respectively, and in peritumoral tissue is identical to that in tumor tissue. Correlation analysis revealed a reliable direct relationship in the studied groups for all parameters, while in the peritumoral tissue of hypertensive patients, the relationship between the average blood pressure and the RAS peptide and enzymes content had a higher tightness.Conclusion. An increase in the levels of AT1 and AT2, ACE and ACE2 in the tumor tissues and peritumoral tissue in patients with localized KC, regardless of the presence of arterial hypertension at initially higher values in hypertensive patients, was shown. The presence of arterial hypertension in patients with KC changes the metabolism of local RAS in peritumoral tissue and is associated with an increase in the correlation between changes in the components of RAS and arterial hypertension.

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Joseph Rudinger memorial lecture: Unexpected functions of angiotensin converting enzyme, beyond its enzymatic activity

Martinez

2017

Journal of Peptide Science

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Angiotensin converting enzyme (ACE) is a well-known enzyme, largely studied for its action on hypertension, as it produces angiotensin II from angiotensin I. This paper describes two original behaviours of ACE. We showed that ACE could hydrolyse gastrin, a neuropeptide from the gastrointestinal tract, releasing the C-terminal amidated dipeptide H-Asp-Phe-NH . This dipeptide is believed to be involved in the gastrin-induced acid secretion in the stomach. This hypothetic mechanism of action of gastrin resulted in a strategy to rationally design gastrin receptor antagonists. Beyond, we showed that the brain renin angiotensin system (RAS) could be activated by a new characterized peptide named acein, resulting in stimulation of dopamine release within the striatum. This new and original 'receptor-like' activity for brain membrane-bound ACE is quite significant taking into account the role of dopamine in the brain, particularly in neurodegenerative diseases. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration

Cited by 29 publications

References 75 publications

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Tissue synthesis of some components of the renin-angiotensin system in hypertensive patients with localized kidney cancer

Joseph Rudinger memorial lecture: Unexpected functions of angiotensin converting enzyme, beyond its enzymatic activity

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