Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice.

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. 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. Smad3 mediates diabetic cardiac hypertrophy, fibrosis, and diastolic dysfunction, while preserving normal cardiac geometry and maintaining the integrity of the vascular wall.

Biernacka A ，Cavalera M ，Wang J ，Russo I ，Shinde A ，Kong P ，Gonzalez-Quesada C ，Rai V ，Dobaczewski M ，Lee DW ，Wang XF ，Frangogiannis NG ... -  《-》

Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction.

Alex L ，Russo I ，Holoborodko V ，Frangogiannis NG ... -  《-》

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure.

Left ventricular dysfunction increases left atrial pressures and causes atrial remodeling. In human subjects, increased left atrial size is a powerful predictor of mortality and adverse events in a broad range of cardiac pathologic conditions. Moreover, structural remodeling of the atrium plays an important role in the pathogenesis of atrial tachyarrhythmias. Despite the potential value of the atrium in assessment of functional endpoints in myocardial disease, atrial pathologic alterations in mouse models of left ventricular disease have not been systematically investigated. Our study describes the geometric, morphologic, and structural changes in experimental mouse models of cardiac pressure overload (induced through transverse aortic constriction), myocardial infarction, and diabetes. Morphometric and histological analysis showed that pressure overload was associated with left atrial dilation, increased left atrial mass, loss of myofibrillar content in a subset of atrial cardiomyocytes, atrial cardiomyocyte hypertrophy, and atrial fibrosis. In mice undergoing nonreperfused myocardial infarction protocols, marked left ventricular systolic dysfunction was associated with left atrial enlargement, atrial cardiomyocyte hypertrophy, and atrial fibrosis. Both infarcted animals and pressure overloaded mice exhibited attenuation and perturbed localization of atrial connexin-43 immunoreactivity, suggesting gap junctional remodeling. In the absence of injury, obese diabetic db/db mice had diastolic dysfunction associated with atrial dilation, atrial cardiomyocyte hypertrophy, and mild atrial fibrosis. Considering the challenges in assessment of clinically relevant functional endpoints in mouse models of heart disease, study of atrial geometry and morphology may serve as an important new tool for evaluation of ventricular function.

Hanif W ，Alex L ，Su Y ，Shinde AV ，Russo I ，Li N ，Frangogiannis NG ... -  《-》

Partial inhibition of activin receptor-like kinase 4 attenuates pressure overload-induced cardiac fibrosis and improves cardiac function.

Li CY ，Chen YH ，Wang Q ，Hou JW ，Wang H ，Wang YP ，Li YG ... -  《-》

Adaptive and maladptive effects of SMAD3 signaling in the adult heart after hemodynamic pressure overloading.

Divakaran V ，Adrogue J ，Ishiyama M ，Entman ML ，Haudek S ，Sivasubramanian N ，Mann DL ... -  《-》