Abstract 20277: Administration of a TGF-β Antagonist Antibody Following Myocardial Infarction has Beneficial Effects on Cardiac Remodeling
TGF-β is a pleiotropic cytokine induced in myocardial infarction (MI) which plays a prominent role in cardiac repair. However, whether TGF-β's role is beneficial or detrimental is controversial. During the inflammatory phase beginning post MI TGF-β may be beneficial in cardiac repair, while later in the proliferative and maturation phases it contributes to cardiac fibrosis and remodeling. We hypothesized that TGF-β antagonism during the inflammatory and proliferative phases of MI would result in reduced fibrosis and improve cardiac function. We monitored the expression of the three TGF-β isoforms and several TGF-β regulated genes on days (d) 1, 3, and 7 post MI in a Lewis rat (n=5) model of 1 hour ischemia followed by reperfusion (IR). TGF-β1 and 2 expression increased significantly (p<0.05) at day 1 (3x and 10x, respectively), whereas TGF-β3 expression increased 3.5 fold (p<0.05) at d3 and d7. When IR rats received a TGF-β antagonist antibody (1D11, 5 mg/kg IV), starting on d3 post MI and every 3 days until sacrifice on day 7 or 12, 1D11 administration resulted in significant decreases in TGF-β1-3 and the evaluated TGF-β regulated genes compared to vehicle controls. To evaluate TGF-β antagonism on cardiac remodeling and function, IR rats (minimum n=7/group) were given 1D11 (5 mg/kg IV) starting on either d0 (2 hr post reperfusion), d3 or d5 post IR, or vehicle starting at d0, and continued every 3 days for 28 days. Similar results were seen with vehicle and the control antibody. 1D11 administration significantly (p<0.05) reduced the fibrosis (% of LV and septum by weight) compared to vehicle (10.6±0.8) when initiated at d0 (6.9±0.6), d3 (6.3±0.7) and d5 (6.4±0.7). Echocardiography was used at d28 to evaluate cardiac function. 1D11 significantly (p<0.05) improved ejection fraction compared to vehicle (43±4%) with administration starting at d3 (60.2±3.5%) and d5 (54±3%). 1D11 also significantly improved anterior wall thickness and thickening, and reduced hypertrophy in the posterior wall when initiated at d0, d3 or d5. These data suggest that antagonizing TGF-β 0 to 5 days after MI leads to decreased cardiac fibrosis, retention of functional myocardium, and improved cardiac function and remodeling.
- © 2010 by American Heart Association, Inc.