Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension

Arruda, R M P; Peotta, Veronica A.; Meyrelles, Silvana S.; Vasquez, Elisardo C.

doi:10.1161/01.hyp.0000182154.61862.52

Cited by 46 publications

(67 citation statements)

References 29 publications

(26 reference statements)

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“…In our study, apoE-deficient mice showed high total serum cholesterol levels, in agreement with results from the investigators who introduced this murine model (18,19) and with previous studies from our group (20,21). We observed that orally administered rapamycin increased total cholesterol levels in apoE-deficient mice fed a normal rodent diet compared with untreated animals.…”

Section: Discussionsupporting

confidence: 92%

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

Gadioli

Nogueira

Arruda

et al. 2009

Braz J Med Biol Res

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Section: Discussionsupporting

confidence: 92%

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

Gadioli

Nogueira

Arruda

et al. 2009

Braz J Med Biol Res

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“…4,5 This is accompanied by increased vasoconstrictor response to angiotensin II (Ang II). 6 This development can be drastically accelerated by a highfat Western diet. 7 Angiotensin II, the main effector of the renin-angiotensin system, contributes to the development of impaired vascular function in apoE(−/−) mice.…”

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confidence: 99%

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

et al. 2014

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Abstract-Apolipoprotein E-deficient (apoE(−/−)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)(1-7) treatment ameliorates endothelial dysfunction in apoE(−/−) mice. However, the mechanism of Ang(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang(1-7) function, we used apoE(−/−) and wildtype mice fed on Western diet that were treated via osmotic minipumps either with Ang(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(−/−) compared with wildtype mice. This apoE(−/−)specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC 20 ), causing renal vasoconstriction. Here, we provide evidence that chronic Ang(1-7) treatment attenuated the renal pressor response to Ang II in apoE(−/−) mice to wildtype levels. Ang(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogenactivated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogenactivated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(−/−) but not in apoE(−/−) mice treated with Ang(1-7). Moreover, Ang(1-7) treatment had no effect in Mas(−/−)/apoE(−/−) doubleknockout mice confirming the specificity of Ang (1-

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“…5,5Ј,6,6Ј-Tetrachloro-1,1Ј,3,3Ј-tetraethylbenzimidazolyl carbocyanine iodide (JC-1) and Amplex Red were obtained from molecular probes (Carlsbad, Calif). 1-Hydroxy-4-phosphono-oxy-2,2,6,6-tetramethylpiperidine (PPH) and bis- (2,2,5, …”

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confidence: 99%

“…[1][2][3] Reactive oxygen species (ROS) play key roles in these processes. 4,5 In addition to vascular NADPH oxidase-derived ROS, Ang II has been shown to stimulate mitochondrial dysfunction in cardiac, renal, and vascular smooth muscle cells.…”

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confidence: 99%

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Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction

Doughan

Harrison²,

Dikalov³

2008

Circulation Research

617

243

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Abstract-Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO˙) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO˙was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography -based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H 2 O 2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), N G -nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22 phox subunit of NADPH oxidase with small interfering RNA also inhibited Ang II-mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II-induced decrease in endothelial NO˙and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO˙and O 2 . generation, which in turn has ramifications for development of endothelial dysfunction. (Circ Res. 2008;102:488-496.)Key Words: mitochondria Ⅲ angiotensin II Ⅲ endothelial cells Ⅲ oxidative stress A ngiotensin (Ang) II mediates endothelial dysfunction and promotes vascular inflammation and atherogenesis. [1][2][3] Reactive oxygen species (ROS) play key roles in these processes. 4,5 In addition to vascular NADPH oxidase-derived ROS, Ang II has been shown to stimulate mitochondrial dysfunction in cardiac, renal, and vascular smooth muscle cells. 6 -9 Dysfunctional mitochondria, in turn, produce excessive amounts of ROS such as superoxide (O 2 . ), hydrogen peroxide (H 2 O 2 ), and peroxynitrite (ONOO Ϫ ). 10,11 This overproduction of mitochondrial ROS has been implicated in neurodegenerative diseases, ischemia reperfusion injury, atherosclerosis and aging. [12][13][14][15][16] Moreover, recent studies have demonstrated that mitochondrial ROS levels can be decreased by overexpression of either manganese superoxide dismutase or the peroxiredoxins 3 or 5 and that this protects against mitochondrial ...

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Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension

Cited by 46 publications

References 29 publications

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction

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