Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice

Anna Biernacka, Michele Cavalera, Junhong Wang, Ilaria Russo, Arti V. Shinde, Ping Kong, Carlos Gonzalez-Quesada, Vikrant Rai, Marcin Dobaczewski, Dong Wook Lee, Xiao Fan Wang, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

40 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)788-798
Number of pages11
JournalCirculation: Heart Failure
Volume8
Issue number4
DOIs
StatePublished - May 1 2015

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Obese Mice
Dilatation
Fibrosis
Cardiomegaly
Hypertrophy
Blood Vessels
Diastolic Heart Failure
Haploinsufficiency
Spontaneous Rupture
Adiposity
Transforming Growth Factors
Leptin
Matrix Metalloproteinases
Cardiac Myocytes
Compliance
Weight Gain
Aorta
Insulin Resistance
Myocardium
Diabetes Mellitus

Keywords

  • Diabetes mellitus
  • Diabetic cardiomyopathies
  • Fibrosis
  • Obesity
  • TGF-β

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice. / Biernacka, Anna; Cavalera, Michele; Wang, Junhong; Russo, Ilaria; Shinde, Arti V.; Kong, Ping; Gonzalez-Quesada, Carlos; Rai, Vikrant; Dobaczewski, Marcin; Lee, Dong Wook; Wang, Xiao Fan; Frangogiannis, Nikolaos G.

In: Circulation: Heart Failure, Vol. 8, No. 4, 01.05.2015, p. 788-798.

Research output: Contribution to journalArticle

Biernacka, A, Cavalera, M, Wang, J, Russo, I, Shinde, AV, Kong, P, Gonzalez-Quesada, C, Rai, V, Dobaczewski, M, Lee, DW, Wang, XF & Frangogiannis, NG 2015, 'Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice', Circulation: Heart Failure, vol. 8, no. 4, pp. 788-798. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001963
Biernacka, Anna ; Cavalera, Michele ; Wang, Junhong ; Russo, Ilaria ; Shinde, Arti V. ; Kong, Ping ; Gonzalez-Quesada, Carlos ; Rai, Vikrant ; Dobaczewski, Marcin ; Lee, Dong Wook ; Wang, Xiao Fan ; Frangogiannis, Nikolaos G. / Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice. In: Circulation: Heart Failure. 2015 ; Vol. 8, No. 4. pp. 788-798.
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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. 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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AU - Cavalera, Michele

AU - Wang, Junhong

AU - Russo, Ilaria

AU - Shinde, Arti V.

AU - Kong, Ping

AU - Gonzalez-Quesada, Carlos

AU - Rai, Vikrant

AU - Dobaczewski, Marcin

AU - Lee, Dong Wook

AU - Wang, Xiao Fan

AU - Frangogiannis, Nikolaos G.

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N2 - 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. 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.

AB - 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. 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.

KW - Diabetes mellitus

KW - Diabetic cardiomyopathies

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KW - Obesity

KW - TGF-β

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