Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice.
Abstract | BACKGROUND: METHODS AND RESULTS: We generated leptin-resistant db/db Smad3 null mice and db/db Smad3+/- animals. Smad3 haploinsufficiency did not affect metabolic function in db/db mice, but protected from myocardial diastolic dysfunction, while causing left ventricular chamber dilation. Improved cardiac compliance and chamber dilation in db/db Smad3+/- animals were associated with decreased cardiomyocyte hypertrophy, reduced collagen deposition, and accentuated matrix metalloproteinase activity. Attenuation of hypertrophy and fibrosis in db/db Smad3+/- hearts was associated with reduced myocardial oxidative and nitrosative stress. db/db Smad3 null mice had reduced weight gain and decreased adiposity associated with attenuated insulin resistance, but also exhibited high early mortality, in part, because of spontaneous rupture of the ascending aorta. Ultrasound studies showed that both lean and obese Smad3 null animals had significant aortic dilation. Aortic dilation in db/db Smad3 null mice occurred despite reduced hypertension and was associated with perturbed matrix balance in the vascular wall. CONCLUSIONS: Smad3 mediates diabetic cardiac hypertrophy, fibrosis, and diastolic dysfunction, while preserving normal cardiac geometry and maintaining the integrity of the vascular wall.
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Authors | Anna Biernacka, Michele Cavalera, Junhong Wang, Ilaria Russo, Arti Shinde, Ping Kong, Carlos Gonzalez-Quesada, Vikrant Rai, Marcin Dobaczewski, Dong-Wook Lee, Xiao-Fan Wang, Nikolaos G Frangogiannis |
Journal | Circulation. Heart failure
(Circ Heart Fail)
Vol. 8
Issue 4
Pg. 788-98
(Jul 2015)
ISSN: 1941-3297 [Electronic] United States |
PMID | 25985794
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 American Heart Association, Inc. |
Chemical References |
- Smad3 Protein
- Smad3 protein, mouse
- Transforming Growth Factor beta
- Matrix Metalloproteinases
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Topics |
- Animals
- Aorta
(metabolism, pathology, physiopathology)
- Aortic Aneurysm
(etiology, genetics, metabolism, pathology, physiopathology)
- Aortic Rupture
(etiology, metabolism, pathology, physiopathology)
- Cardiomegaly
(etiology, genetics, metabolism, pathology, physiopathology)
- Diabetic Cardiomyopathies
(etiology, genetics, metabolism, pathology, physiopathology)
- Dilatation, Pathologic
- Disease Models, Animal
- Female
- Fibrosis
- Male
- Matrix Metalloproteinases
(metabolism)
- Mice, Inbred C57BL
- Mice, Knockout
- Myocardium
(metabolism, pathology)
- Obesity
(complications, genetics, metabolism, physiopathology)
- Signal Transduction
- Smad3 Protein
(deficiency, metabolism)
- Time Factors
- Transforming Growth Factor beta
(metabolism)
- Vascular Remodeling
- Ventricular Dysfunction, Left
(etiology, genetics, metabolism, pathology, physiopathology)
- Ventricular Remodeling
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