Losartan Inhibits Vascular Smooth Muscle Cell Proliferation through Activation of AMP-Activated Protein Kinase

Kim, Jung Eun; Choi, Hyoung Chul

doi:10.4196/kjpp.2010.14.5.299

Cited by 33 publications

(19 citation statements)

References 32 publications

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“…In vascular smooth muscle cells, however, losartan alone has no significant effect on proliferation [49], and, in the human endometrial adenocarcinoma (HEC-59) cell line, losartan at concentrations between 1 and 10 µmol l -1 induces a slight increase [50]. Losartan, in the presence of ATII, prevents the increase in proliferation produced by ATII alone (Fig.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…One study found that globular adiponectin (gAd) inhibits AngII-induced NF-κB activation in hypertrophic neonatal rat ventricular myocytes (NRVMs) via AMPK activation [103]. Another study reported that losartan activated AMPK activation, inhibited the AngII-induced VSMC proliferation by cell cycle arrest [104]. Another research claimed that adiponectin weakens AngII-induced oxidative stress through cAMP-Epac and AMPK signal pathways in renal tubular cells [105].…”

Section: Angii and Ampk In Kidneymentioning

confidence: 99%

AMPK: a balancer of the renin–angiotensin system

Liu

et al. 2019

Bioscience Reports

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The renin–angiotensin system (RAS) is undisputedly well-studied as one of the oldest and most critical regulators for arterial blood pressure, fluid volume, as well as renal function. In recent studies, RAS has also been implicated in the development of obesity, diabetes, hyperlipidemia, and other diseases, and also involved in the regulation of several signaling pathways such as proliferation, apoptosis and autophagy, and insulin resistance. AMP-activated protein kinase (AMPK), an essential cellular energy sensor, has also been discovered to be involved in these diseases and cellular pathways. This would imply a connection between the RAS and AMPK. Therefore, this review serves to draw attention to the cross-talk between RAS and AMPK, then summering the most recent literature which highlights AMPK as a point of balance between physiological and pathological functions of the RAS.

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“…Importantly, metformin, one of the mostly widely used anti-diabetic drugs which is reported to activate AMPK in vivo, are reported to lower blood pressures in various models of hypertensive animals and in patients with or without diabetes. Interestingly, recent studies report that telmisartan and losartan, selective angiotensin II receptor blockers, is reported to inhibit VSMC proliferation 33 and glucose uptake by activating AMPK 34 . Taken together, AMPK inhibition might contribute to the initiation and progression of hypertension and AMPK is a novel therapeutic target for effective treatments of hypertension, especially in metabolic syndrome such as obesity and diabetes.…”

Section: Perspectivesmentioning

confidence: 99%

Inhibition of the AMP-Activated Protein Kinase-α2 Accentuates Agonist-Induced Vascular Smooth Muscle Contraction and High Blood Pressure in Mice

et al. 2011

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The aim of the present study was to determine the effects and molecular mechanisms by which AMP-activated protein kinase (AMPK) regulates smooth muscle contraction and blood pressure in mice. In cultured human vascular smooth muscle cells (HMSC), we observed that activation of AMPK by AICAR (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside) inhibited agonists-induced phosphorylation of myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1). Conversely, AMPK inhibition with pharmacologic or genetic means potentiated agonists-induced the phosphorylation of MLC and MYPT1 while inhibited both Ras homolog gene family, member A (RhoA) and Rho-associated kinase (ROCK) activity. Further, AMPK activation or ROCK inhibition with Y27632 abolished agonists-induced phosphorylation of MLC and MYPT1. Gene silencing of p190-guanosine triphosphatase-activating protein (p190-GAP) abolished the effects of AMPK activation on MLC, MYPT1, and RhoA in HSMC. Ex vivo analyses revealed that agonist-induced contractions of the mesenteric artery and aortas were stronger in both AMPKα1−/− and AMPKα2−/− knockout mice than in wild-type mice. Inhibition of ROCK with Y27632 normalized agonist-induced contractions of AMPKα1−/− and AMPKα2−/− vessels. AMPKα2−/− mice had higher blood pressure along with decreased serine phosphorylation of p190-guanosine triphosphatase-activating protein (p190-GAP). Finally, inhibition of the RhoA/ROCK pathway with Y27632, which suppressed MYPT1 and MLC phosphorylation, lowered blood pressure in AMPKα2−/− mice. In conclusion, AMPK decreases vascular smooth muscle cell contractility by inhibiting p190-GAP-dependent RhoA activation, indicating AMPK may be a new therapeutic target in lowering high blood pressure.

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Losartan Inhibits Vascular Smooth Muscle Cell Proliferation through Activation of AMP-Activated Protein Kinase

Cited by 33 publications

References 32 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

AMPK: a balancer of the renin–angiotensin system

Inhibition of the AMP-Activated Protein Kinase-α2 Accentuates Agonist-Induced Vascular Smooth Muscle Contraction and High Blood Pressure in Mice

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