Lamr1 functional retroposon causes right ventricular dysplasia in mice

Asano, Yosh ihiro; Takashima, Seiji; Asakura, Masanori; Shintani, Yasunori; Liao, Yulin; Minamino, Tetsuo; Asanuma, Hiroshi; Shoji, Shuichi; Kim, Jiyoong; Ogai, Akiko; Fukushima, Tomi; Oikawa, Yumiko; Okazaki, Yasushi; Kaneda, Yasufumi; Sato, Manabu; Miyazaki, Jun‐ichi; Kitamura, Soichiro; Tomoike, Hitonobu; Kitakaze, Masafumi; Hori, Masatsugu

doi:10.1038/ng1294

Cited by 48 publications

(30 citation statements)

References 34 publications

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“…However, the model suffers from an undefined genetic basis. Recently, a mouse model was described in which transcription of an intronic retroposon in laminin receptor 1 led a phenotype resembling right ventricular dysplasia (40). Detailed examination showed a distinct phenotype characterized by epicardial fibrosis and, more importantly, the absence of adipocytic infiltration of myocardium and ventricular arrhythmias (40).…”

Section: Discussionmentioning

confidence: 99%

Suppression of canonical Wnt/ -catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy

Garcia-Gras

Lombardi

Giocondo

et al. 2006

Journal of Clinical Investigation

553

619

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Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/b-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.

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Section: Discussionmentioning

confidence: 99%

Suppression of canonical Wnt/ -catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy

Garcia-Gras

Lombardi

Giocondo

et al. 2006

Journal of Clinical Investigation

553

619

View full text Add to dashboard Cite

show abstract

“…The histological analysis of the right ventricle showing massive fibrofatty replacement of the myocardium remains a hallmark of ARVC/D. Several animal models exist, including dogs, cats, minks, and mice 21 , 22 , 23 to study this rare disease entity.…”

Section: Pathologymentioning

confidence: 99%

Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare “disease of the desmosome” with multiple clinical presentations

2009

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“…19 The Quantitect SYBR Green RT-PCR kit (Qiagen) was used to perform amplifications with the One-step protocol as described by the manufacturer.…”

Section: Rna Analysismentioning

confidence: 99%

Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

et al. 2004

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Background-The blockade of ␤-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective ␤ 1 -blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway. Methods and Results-In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N G -nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70Ϯ0.42 in TAC, 6.61Ϯ0.44 with celiprolol 100 mg · kg Ϫ1 · d Ϫ1 PO, PϽ0.01) and the ratio of lung weight to body weight (mg/g) (10.27Ϯ1.08 in TAC, 7.11Ϯ0.70 with celiprolol 100 mg · kg Ϫ1 · d Ϫ1 PO, PϽ0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice. Conclusions-These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective ␤ 1 -adrenergic receptor blockade and NO-dependent pathway.

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Lamr1 functional retroposon causes right ventricular dysplasia in mice

Cited by 48 publications

References 34 publications

Suppression of canonical Wnt/ -catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy

Suppression of canonical Wnt/ -catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare “disease of the desmosome” with multiple clinical presentations

Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

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