Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice

Yamamoto, Keita; Shioi, Tetsuo; Uchiyama, Köji; Miyamoto, Tadashi; Sasayama, Shígetake; Matsumori, Akira

doi:10.1016/j.jacc.2003.07.021

Cited by 37 publications

(26 citation statements)

References 39 publications

(57 reference statements)

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“…However, a number of other ACE-inhibitors have also been shown to inhibit apoptosis in other tissues, including enalapril (32), quinaprilat (36), and captopril (35), as well as other inhibitors of components of the ACE/Angiotensin signaling cascade, such as angiotensin receptor blockers (30,40).…”

Section: Discussionmentioning

confidence: 99%

“…ACE plays a role in apoptosis in a wide variety of tissues, including neural tissues, vascular endothelium, smooth muscle, and fetal adrenals (21,(37)(38)(39). Interestingly, ACE and Ang II have also been linked to upregulation of TNF-α (40). In fact, apoptosis attributable to TNF-α was actually shown to be dependent on the binding of Ang II to its receptors on alveolar epithelial cells (8).…”

Section: Introductionmentioning

confidence: 99%

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Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

et al. 2007

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Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point; as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

et al. 2007

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“…In respect to myocarditis, IKK/NF-κB is likely of importance, but its function may depend on the etiology of the disease (12)(13)(14)(15). One of the main causes of myocarditis in humans-and, presumably, its sequela, dilated cardiomyopathy-is infection with enteroviruses.…”

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confidence: 99%

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Maier

Schips²,

Wietelmann³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

158

117

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Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b + cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.transcription factors | transgenic mice

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“…Despite the lack of extensive studies in pediatric patients, administration of carvedilol has been found to be associated with improvement of left ventricle function and clinical symptoms and normalization of antioxidant enzyme activity (Bajcetic et al, 2008). Similar to effects of blockers, ACE inhibitors and angiotensin receptor blockers have been documented to lessen viral myocardial injury in murine models (Yamamoto et al, 2003). It is also proposed that early introduction of beta-blockers and ACE inhibitors might prevent the remodelling that advances to dilated cardiomyopathy (Ellis&DiSalvo, 2007).…”

Section: Treatmentmentioning

confidence: 99%

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management

Tavli¹,

Güven²

2011

Myocarditis

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Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice

Abstract: These results indicate that the AT(1)R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II via the NF-kB/cytokine pathway.

Cited by 37 publications

References 39 publications

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management

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