Abstract 16613: Smad3 Loss is Associated with Aortic Dilation and Spontaneous Aortic Rupture in Lean and in Obese Diabetic Db/db Mice
Fibrosis and diastolic dysfunction are the hallmarks of diabetic heart disease; activation of TGF-β/Smad3 may mediate fibrosis in diabetic hearts. We used leptin resistant obese/diabetic db/db mice in order to study the role of Smad3 in remodeling of the diabetic heart. Db/db mice developed concentric hypertrophy and diastolic dysfunction; however, systolic function was preserved. Collagen deposition was increased in db/db hearts; fibrotic changes were preceded by Smad3 activation. In order to examine the role of Smad3 in remodeling of the db/db heart we generated db/db Smad3 -/- (dbSKO) mice. dbSKO animals exhibited high early mortality in comparison to db/db mice (p<0.01); surprisingly, more than 50% of deaths were due to spontaneous aortic rupture. Echocardiographic analysis showed that Smad3 loss in db/db mice resulted in aortic dilation. Lean Smad3 -/- mice also had increased mortality, aortic dilation and increased incidence of aortic rupture, associated with reduced aortic collagen and an increased MMP-2:TIMP-1 ratio. In contrast, db/db Smad3 +/- heterozygotes (db/het) had similar survival curves, comparable weight gain and fat content with db/db mice. Although db/het mice had enlarged aortas when compared to db/db animals, they showed a very low incidence of aortic rupture. Hemodynamic analysis showed that, in comparison to db/db mice, db/het animals had attenuated diastolic dysfunction, associated with significant ventricular dilation (LVEDV, db/db: 82.9+4.7 vs. db/het: 125.6+6.4; p<0.01) and mild non-progressive systolic dysfunction (FS, db/db: 42.8+2.9 vs.db/het: 29.1+2.7; p<0.01). The cardiac alterations observed in db/het mice were associated with reduced collagen deposition and increased MMP activity. Our findings suggest a critical role for Smad3 in matrix homeostasis in the cardiovascular system. Although Smad3 disruption prevents fibrosis and diastolic dysfunction of the diabetic heart, it is associated with excessive matrix degradation, resulting in chamber dilation and modest systolic dysfunction. More importantly, Smad3 loss results in perturbations in aortic matrix leading to dilation and rupture. These findings raise a word of caution regarding the use of TGF-β/Smad3 inhibition to prevent fibrosis.
- © 2012 by American Heart Association, Inc.