Hypertension (Dallas, Tex. 1979), 2010-08, Vol.56 (2), p.232-239
2010
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Details
- Autor(en) / Beteiligte
- Titel
- Tumor Suppressor A20 Protects Against Cardiac Hypertrophy and Fibrosis by Blocking Transforming Growth Factor-β–Activated Kinase 1–Dependent Signaling
- Ist Teil von
- Hypertension (Dallas, Tex. 1979), 2010-08, Vol.56 (2), p.232-239
- Ort / Verlag
- Hagerstown, MD: American Heart Association, Inc
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- A20 or tumor necrosis factor–induced protein 3 is a negative regulator of nuclear factor κB signaling. A20 has been shown previously to attenuate cardiac hypertrophy in vitro and postmyocardial infarction remodeling in vivo. In the present study, we tested the hypothesis that overexpression of A20 in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human A20 expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding in A20 transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by echocardiography, as well as by pathological and molecular analyses of heart samples. Constitutive overexpression of human A20 in the murine heart attenuated the hypertrophic response and markedly reduced inflammation, apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased A20 levels in response to hypertrophic stimuli. Western blot experiments further showed A20 expression markedly blocked transforming growth factor-β–activated kinase 1–dependent c-Jun N-terminal kinase/p38 signaling cascade but with no difference in either extracellular signal-regulated kinase 1/2 or AKT activation in vivo and in vitro. In cultured neonatal rat cardiac myocytes, [3H]proline incorporation and Western blot assays revealed that A20 expression suppressed transforming growth factor-β–induced collagen synthesis and transforming growth factor-β–activated kinase 1–dependent Smad 2/3/4 activation. In conclusion, A20 improves cardiac functions and inhibits cardiac hypertrophy, inflammation, apoptosis, and fibrosis by blocking transforming growth factor-β–activated kinase 1–dependent signaling.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0194-911XeISSN: 1524-4563DOI: 10.1161/HYPERTENSIONAHA.110.149963Titel-ID: cdi_proquest_miscellaneous_733984028
- Format
- –
- Schlagworte
- Animals, Animals, Newborn, Apoptosis, Arterial hypertension. Arterial hypotension, Biological and medical sciences, Blood and lymphatic vessels, Body Weight, Cardiology. Vascular system, Cardiomegaly - genetics, Cardiomegaly - pathology, Cardiomegaly - prevention & control, Disease Models, Animal, DNA-Binding Proteins, Endomyocardial Fibrosis - genetics, Endomyocardial Fibrosis - pathology, Endomyocardial Fibrosis - prevention & control, Fibroblasts - cytology, Fibroblasts - physiology, Heart, Heart - anatomy & histology, Heart failure, cardiogenic pulmonary edema, cardiac enlargement, Humans, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - physiology, MAP Kinase Kinase Kinases - antagonists & inhibitors, MAP Kinase Kinase Kinases - metabolism, MAP Kinase Kinase Kinases - physiology, Medical sciences, Mice, Mice, Transgenic, Muscle Cells - cytology, Muscle Cells - physiology, Nuclear Proteins - genetics, Nuclear Proteins - physiology, Organ Size, Rats, Stress, Mechanical, Transforming Growth Factor beta1 - antagonists & inhibitors, Tumor Necrosis Factor alpha-Induced Protein 3