Abstract 3: Targeted Inhibition Of Transforming Growth Factor Beta In Cardiac Myocytes Prevents Myocardial Rupture After Infarction
Introduction Coronary artery disease is the leading cause of death and myocardial infarction (MI) its most severe manifestation.TGFb is a major switch governing the myocardial response to injury and global inhibition is detrimental following MI. Recently, cell-specific gene manipulation models have enabled investigation of cardiomyocyte (CM) versus non-CM TGFb signaling on maladaptive remodeling. We found CM TGFb to be central to pressure-overload disease. Here, we tested the hypothesis that CM TGFb modifies acute post-MI remodeling, and thus benefits rather than worsens outcome as observed with antibody-based inhibition that primarily targets interstitial/vascular cells.
Methods Mice with cardiac-specific conditional knockdown of TgfbR1 or 2 (aMHC - MCM TgfbR fl/fl) or injection of TGFb-neutralizing antibody were subjected to proximal LAD-ligation and followed by echocardiography and continuous ECG monitoring. Expression and activity of the major matrix metalloproteinases MMP2/MMP9 and TIMP1 were assessed by qRT-PCR, immunoblot, and zymography, respectively. Only mice surviving >24h after surgery (>90%) were included in analyses.
Results LAD ligation decreased fractional shortening on day 1 to 18±2% (61±1% in sham animals) with no differences between genotypes (n≥8). Similarly, echocardiographic parameters of myocardial dimensions and function did not differ at weeks 1 or 3. Early mortality (day 4 - 10) was strikingly lower in knockdown mice as compared to controls (10% vs 48%, p<0.05, n≥10). Remarkably, systemic TGFb inhibition resulted in 100% mortality (n=8) by day 5. The cause of death was established by necropsy and continuous ECG monitoring and was myocardial rupture in all cases. MMP9 expression and gelatinolytic activity was reduced by CM TGFbR knockdown at day 3 after MI, as was TIMP1 expression, while MMP2 expression/activity was not altered.
Conclusion TGFb inhibition exhibits differential effects in wound healing following MI. Where global inhibition is deleterious, CM-targeted knockdown powerfully protects the heart from rupture. This highlights potent cross-talk between the CM TGFb signal and matrix remodeling and the importance of targeted inhibition to benefit cardiac disease.
- © 2012 by American Heart Association, Inc.