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 (TGF)-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 and obesity. Methods and Results We generated leptin-resistant db/db Smad3 null mice (dbSKO) and db/db Smad3 +/- animals (dbShet). 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 dbShet animals was associated with decreased cardiomyocyte hypertrophy, reduced collagen deposition and accentuated matrix metalloproteinase (MMP) activity. Attenuation of hypertrophy and fibrosis in dbShet hearts was associated with reduced myocardial oxidative and nitrosative stress. dbSKO mice had reduced weight gain and decreased adiposity associated with attenuated insulin resistance, but also exhibited high early mortality, in part due to spontaneous rupture of the ascending aorta. Ultrasound studies showed that both lean and obese Smad3 null animals had significant aortic dilation. Aortic dilation in dbSKO 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.

Chronic Heart Failure and Inflammation

“…133 Although the relationship between reactive oxygen species and macrophage recruitment requires further investigation, this represents an interesting link between Smad3/TGF-β signaling and oxidative stress in the diabetic myocardium.…”

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…Moreover, it should be emphasized that, because of its broad effects on many cell types, targeting TGF-β may carry significant risks (123). A large body of evidence suggests that disruption of the TGF-β/Smad axis promotes aortic aneurysm formation and rupture (124)(125)(126). Thus attempts for clinical translation of TGF-β/Smad inhibition strategies should exclude patients vulnerable to the potentially adverse consequences of Smad3 disruption on vascular remodeling.…”

Transcriptional control of cardiac fibroblast plasticity

“…CFs isolated from Smad3 -deficient animals secrete less collagen and have fewer ACTA2 positive stress fibers compared to fibroblasts from control animals [78]. Furthermore, loss of Smad3 attenuates fibrotic remodeling in mouse models of MI, idiopathic pulmonary fibrosis, and diabetes mellitus [67, 79, 80]. Animals heterozygous for Smad3 appear to be protected from diabetes-induced cardiac hypertrophy suggesting a dose-dependent role of SMAD3-regulated TGFβ signaling [79].…”

“…Furthermore, loss of Smad3 attenuates fibrotic remodeling in mouse models of MI, idiopathic pulmonary fibrosis, and diabetes mellitus [67, 79, 80]. Animals heterozygous for Smad3 appear to be protected from diabetes-induced cardiac hypertrophy suggesting a dose-dependent role of SMAD3-regulated TGFβ signaling [79]. Expression of the inhibitory SMAD7 is reduced in the infarcted rat heart, which is thought to relieve the repression of the TGFβ-Smad axis and promote fibroblast activation in vivo [81].…”