title: Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice.
abstract: BACKGROUND
  Heart failure in diabetics is associated with cardiac hypertrophy, fibrosis and diastolic dysfunction. Activation of transforming growth factor-β/Smad3 signaling in the diabetic myocardium may mediate fibrosis and diastolic heart failure, while preserving matrix homeostasis. We hypothesized that Smad3 may play a key role in the pathogenesis of cardiovascular remodeling associated with diabetes mellitus and obesity.
  
  
  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.
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Michele
authors.initials: M
authors.lastname: Cavalera
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Junhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Arti
authors.initials: A
authors.lastname: Shinde
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Ping
authors.initials: P
authors.lastname: Kong
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Quesada
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Vikrant
authors.initials: V
authors.lastname: Rai
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Lee
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.).
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (A.B., M.C., J.W., I.R., A.S., P.K., C.G.-Q., V.R., M.D., D.-W.L., N.G.F.); Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., M.D., N.G.F.); and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC (X.-F.W.). nikolaos.frangogiannis@einstein.yu.edu.
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001014:Aortic Aneurysm / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001019:Aortic Rupture / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D051900:Smad3 Protein / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D066253:Vascular Remodeling; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases
keywords: TGF-β; diabetes mellitus; diabetic cardiomyopathies; fibrosis; obesity