Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit

Bodiga, Sreedhar; Zhong, Jiu Chang; Wang, Wang; Basu, Ratnadeep; Lo, Jennifer; Liu, George C.; Guo, Danny; Holland, Steven M.; Scholey, James W.; Penninger, Josef; Kassiri, Zamaneh; Oudit, Gavin Y.

doi:10.1093/cvr/cvr036

Cited by 80 publications

(99 citation statements)

References 44 publications

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“…3, 8 For transmission electron microscopic analysis, samples of mice heart tissues (left ventricles) were immediately cut into small pieces and immersed in 2.5% glutaraldehyde as described previously. 19 The myocardial ultrastructure of the WT and ACE2KO mice was observed on a HITACHI-600 electron microscope (Hitachi, Japan).…”

Section: Echocardiography and Myocardial Ultrastructure Observationmentioning

confidence: 99%

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Myocardial Injury via Activation of the CTGF-Fractalkine Signaling Pathway

Song

Zhang

Zhong

et al. 2013

Circ J

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Section: Echocardiography and Myocardial Ultrastructure Observationmentioning

confidence: 99%

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Myocardial Injury via Activation of the CTGF-Fractalkine Signaling Pathway

Song

Zhang

Zhong

et al. 2013

Circ J

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“…3 Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme, is a monocarboxypeptidase that metabolizes Ang II to yield angiotensin 1-7 (Ang 1-7) and lowers the Ang II/Ang 1-7 ratio. [4][5][6][7][8][9] Ang II receptor blockers that selectively antagonize the AT 1 R became a valid alternative approach to interfere with the renin-angiotensin system axis and also upregulates ACE2, resulting in the generation of Ang 1-7. 10,11 Ang 1-7 acts on the Mas receptor and plays an important role in counteracting the actions of Ang II.…”

mentioning

confidence: 99%

“…10,11 Ang 1-7 acts on the Mas receptor and plays an important role in counteracting the actions of Ang II. [12][13][14][15][16][17][18] Ang II-mediated oxidative stress, cardiac hypertrophy, contractile dysfunction, and fibrosis are exacerbated in ACE2-deficient mice, 5,7 whereas recombinant human ACE2 is able to attenuate these responses and improve cardiac function, with a marked reversal of Ang II-mediated signaling. 6 Many of the cardiac pathological effects of reninangiotensin system activation and Ang II appear to be mediated through ROS, produced by a specific NADPH oxidase-dependent pathway in an AT 1 R-dependent manner.…”

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confidence: 99%

Cardioprotective Effects Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin 1-7 in Experimental Heart Failure in Angiotensin-Converting Enzyme 2–Null Mice

Patel

Bodiga²,

Fan³

et al. 2012

Hypertension

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Abstract-Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT 1 R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT 1 R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice. AT 1 R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47 phox subunits and also by limiting the p47 phox phosphorylation. Biomechanical stress-induced increase in protein kinase C-␣ expression and phosphorylation of extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3␤ were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II-mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2-null hearts were inhibited to similar degree by AT 1 R blockade and stimulation with Ang 1-7. Thus, treatment with the AT 1 R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure-overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways. Key Words: renin-angiotensin system Ⅲ angiotensin 1-7 Ⅲ angiotensin-converting enzyme 2 Ⅲ NADPH oxidase Ⅲ AT 1 receptor Ⅲ heart failure Ⅲ signaling S everal lines of experimental and clinical evidence implicate a key role for the renin-angiotensin system in the pathophysiology of a number of cardiovascular diseases, such as myocardial infarction, hypertension, and heart failure. 1,2Angiotensin II (Ang II), acting via the Ang II type 1 receptor (AT 1 R) and Ang II type 2 receptor, modulates production of reactive oxygen species (ROS), impairing myocardial contractility and extracellular matrix remodeling, thereby negatively impacting on heart function.3 Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme, is a monocarboxypeptidase that metabolizes Ang II to yield angiotensin 1-7 (Ang 1-7) and lowers the Ang II/Ang 1-7 ratio.4-9 Ang II receptor blockers that selectively antagonize the AT 1 R became a valid alternative approach to interfere with the renin-angiotensin system axis and also upregulates ACE2, resulting in the generation of Ang 1-7. 10,11 Ang 1-7 acts on the Mas receptor and plays an important role in counteracting the actions of Ang II. 12-18Ang II-mediated oxidative stress, cardiac hypertrophy, contractile dysfunction, and fibrosis are exacerbated in ACE2-deficient mice, 5,7 whereas recombinant ...

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“…6 Aortic banding of ACE2KO mice exacerbates the progression of LV hypertrophy, LV dilatation, and systolic dysfunction, which is associated with increased NADPH oxidase activity and subsequent oxidative stress, and is amendable to reversal following Ang 1-7 supplementation. 7 Utilizing a different approach, Mercure et al also demonstrated beneficial effects for Ang 1-7 against Ang II-induced adverse remodeling, as transgenic mice that overexpress Ang 1-7 specifically in the heart exhibit a reduction in ventricular fibrosis and LV hypertrophy following a 19-day Ang II infusion. 8 In the Patel et al study, the authors crossed ACE2KO mice with diabetic Akita mice to determine the contribution of ACE2 in the progression of diabetic cardiomyopathy.…”

Section: Article See P 1322mentioning

confidence: 99%

An ACE Up Your Sleeve

Ussher¹,

Lopaschuk²

2012

Circulation Research

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A lthough the renin angiotensin system (RAS) is a well established regulator of blood pressure and intravascular volume, 1 considerable evidence has emerged demonstrating the importance of the RAS directly on the cardiovascular system (please refer to the Figure for description of the enzymatic pathways involved in RAS regulation). Indeed, angiotensin converting enzyme (ACE) inhibitors, which prevent the conversion of angiotensin I into angiotensin II (Ang II), and Ang II receptor type 1 (AT1R) antagonists, which inhibit the receptor-mediated actions of Ang II, have demonstrated direct favorable effects on the heart. These include a reduction in cardiac fibrosis during hypertensive left ventricular (LV) hypertrophy, protection against LV enlargement following myocardial infarction, and reduced LV remodeling following coronary artery bypass graft surgery. 2 Hence, ACE1 is generally thought of as a villain contributing to the development of cardiovascular disease due to its generation of Ang II. Fortunately, the RAS may also have a potential hero in ACE2, which can counter many of the negative consequences of ACE1-produced Ang II. In this issue of Circulation Research, Patel et al 3 demonstrate an important role for the RAS in the development of diabetic cardiomyopathy. If diabetic Akita mice are deficient for ACE2 (Akita/ ACE2KO), the enzyme responsible for converting Ang II into Ang 1-7, a progressive systolic dysfunction occurred that is associated with oxidative stress, excessive extracellular matrix degradation, vascular dysfunction, and impairment of the Akt-signaling pathway. Ang II activation of the AT1R was implicated in these actions, since a 1-month treatment with the AT1R antagonist, irbesartan, reversed this systolic dysfunction, oxidative stress, vascular dysfunction, and Akt signaling in the Akita/ACE2KO mice. Article, see p 1322These findings add to the growing body of evidence implicating a cardioprotective role for ACE2 in cardiovascular diseases. Initial interest in ACE2 as a potential therapeutic target for cardiovascular diseases was engendered by the observation that ace2 mapped to several putative genetic quantitative trait loci associated with hypertension in 3 rodent models of elevated blood pressure. 4 Moreover, the generation of mice deficient for ACE2 (ACE2KO) was associated with a phenotype exhibiting LV contractile dysfunction. 4 Subsequent studies illustrated that ACE2 may be a potential cardioprotective target in a variety of cardiac pathologies. Indeed, ACE2KO mice are more susceptible to ischemic injury, adverse LV remodeling, and LV contractile dysfunction following permanent occlusion of the left anterior descending coronary artery. 5 These effects are prevented by treatment with irbesartan for 3 days prior to left anterior descending coronary artery occlusion and for the duration of the study. 5 Chronic infusion of Ang II into mice also exacerbates pathological hypertrophy, oxidative stress, myo-

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Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit

Cited by 80 publications

References 44 publications

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Myocardial Injury via Activation of the CTGF-Fractalkine Signaling Pathway

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Myocardial Injury via Activation of the CTGF-Fractalkine Signaling Pathway

Cardioprotective Effects Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin 1-7 in Experimental Heart Failure in Angiotensin-Converting Enzyme 2–Null Mice

An ACE Up Your Sleeve

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