Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice

Oudit, Gavin Y.; Kassiri, Zamaneh; Patel, Mikin P.; Chappell, Mark C.; Butany, Jagdish; Backx, Peter H.; Tsushima, Robert G.; Scholey, James W.; Khokha, Rama; Penninger, Josef

doi:10.1016/j.cardiores.2007.04.007

Cited by 223 publications

(204 citation statements)

References 50 publications

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“…In this study, local renal RAS was found to be highly activated, as manifested by the increased ACE expression and Ang II level and decreased ACE2 expression and Ang-(1-7) level in the cortex. As the key peptide of the RAS, Ang II exerts a variety of effects via its type 1 receptor, including vasoconstriction, sodium retention, cell proliferation and apoptosis, proinflammation and oxidative stress (30). Our study confirmed that Ang II promoted cell proliferation and enhanced reactive oxygen species production in cultured GMCs.…”

Section: Discussionsupporting

confidence: 79%

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Liu

Wang

et al. 2010

Mol Med

101

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The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 mg/kg streptozotocin. Eight wks after streptozotocin injection, the diabetic rats were divided into no treatment group, adenoviral (Ad)-ACE2 group, Ad-green flurescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI group. Four wks after treatment, physical, biochemical, and renal functional and morphological parameters were measured. An experiment in cultured glomerular mesangial cells was performed to examine the effects of ACE2 on cellular proliferation, oxidative stress and collagen IV synthesis. In comparison with the Ad-GFP group, the Ad-ACE2 group exhibited reduced systolic blood pressure, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index and renal malondialdehyde level; downregulated transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefits. ACE2 transfection attenuated angiotensin (Ang) II-induced glomerular mesangial cell proliferation, oxidative stress and collagen IV protein synthesis. In conclusion, ACE2 exerts a renoprotective effect similar to that of ACEI treatment. Decreased renal Ang II, increased renal Ang-(1-7) levels, and inhibited oxidative stress were the possible mechanisms involved.

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Section: Discussionsupporting

confidence: 79%

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Liu

Wang

et al. 2010

Mol Med

101

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“…24,25,33 In contrast, ACE2 deficiency causes a marked increase in oxidative stress, which has been attributed to the diminished generation of Ang (1-7) by ACE2 deficiency as a counter regulatory mechanism to Ang II. 45 In addition, cardiac overexpression of Ang(1-7) improved Ang II-dependent cardiac hyper trophy by reducing p38 MAPK activity. 46 Therefore, we hypothesized that other mechanisms, independent from NO, might contribute to the attenuated pressor response to Ang II seen in Ang(1-7)-treated apoE(−/−) mice.…”

Section: Discussionmentioning

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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“…[39][40][41][42][43] Lending support to the role of various RAS components in oxidative injury predisposing to aging are findings that ACE2 null mice are more sensitive to Ang II-mediated oxidative stress and inflammation than wild-type littermates. 44 Moreover, overexpression of ACE2 in the central nervous system reduces oxidative stress and improves autonomic function in mice. 45 A life-prolonging effect of AT 1 receptor blockade has been proposed by a study using mice with targeted disruption of the gene encoding the AT 1A receptor (AT 1A −/− ).…”

Section: Oxygen Free Radicals Are Crucial Molecules Involved In Mitocmentioning

confidence: 99%

Aging and the Renin-Angiotensin System

2012

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Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice

Cited by 223 publications

References 50 publications

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

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

Aging and the Renin-Angiotensin System

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