Abstract 1430: Protective Effect of Smad3 Deficiency on Cardiac Function after Myocardial Infarction
Background: Transforming growth factor-beta’s (TGFβs) transduce their signal via a specific complex of serine/threonine kinase receptors. Upon ligand binding to the TGFβ receptor complex, Smad proteins are phosphorylated and translocated to the nucleus where they regulate transcription of TGFβ target genes. Both Smad2 and Smad3 transduce signals of TGFβ from the cell surface to the nucleus. Smad3 was identified as an essential mediator of TGFβ responses, directly activating genes encoding for TGFβ early targets, while Smad2 was not critical to the majority of gene responses. Interestingly, the TGFβ/Smad3 pathway was shown to play a central role in specific pathological fibrosis in which TGFβ has previously been implicated. Therefore, we hypothesized that Smad3 might prevent scarring after myocardial infarction and improve cardiac function.
Methods and Results: We induced myocardial infarction (MI) by permanent ligation of the LAD in Smad3 KO mice and WT controls. Our first observation was that Smad3 deficiency resulted in myocardial rupture in all null mice 4–5 days post MI. Analyzing RNA/Protein samples, isolated prior to myocardial rupture, showed that Smad3 deficiency results in a decrease in TIMP1 expression (KO 0.4 +/− 0.2 vs Wt 0.8+/−0.3 p<0.05) after MI resulting in increased Matrix Metalloprotease (MMP) activity and subsequent collagen degradation. Next, we pretreated Smad3 deficient and WT mice with doxycycline, a broad-spectrum MMP inhibitor, prior to LAD ligation. Doxycycline treatment rescued Smad3 null mice from dying of cardiac rupture. More strikingly, although WT ligated animals (n=5) show a clear infarct and dilated left ventricle 28 days post MI and impaired function, as determined by MRI (Fractional shortening 23.6 +/− 7.3), Smad3-null mice (n=5), showed almost complete restoration of ventricular damage, wall thickness, and function (Fractional shortening 62.6 +/− 9.5 p<0.05 compared to WT). Histological analysis revealed a cardiac wall almost indistinguishable from healthy WT hearts.
Conclusions: Our results show that Smad3 is extremely important in the response of the ventricle to MI damage. Smad3 inhibition might be very beneficial for myocardial repair if applied within a certain temporary window after MI.