Abstract 15385: Integrin Alpha 11 is a Critical Regulator of Cardiac Remodelling, Fibrosis and Infarct Formation Following Myocardial Infarction

Abstract

Cardiac fibrosis (CF), a key feature of cardiac remodelling, defined as the accumulation of excessive amounts of extracellular matrix (ECM), in response to injuries such as myocardial infarction (MI). Cardiac fibroblasts within and surrounding the injured area respond to biochemical and mechanical stimuli transforming into myofibroblasts and begin to secrete collagen. Long term collagen production reduces ventricular compliance and ultimately results in further cardiac dysfunction leading to heart failure. Mechanical activation of collagen production is understood to be a significant mediator of cardiac fibrosis. However, the mechanisms via which mechanical stimuli initiate cardiac fibroblast activation are not well understood. Therefore, we sort to investigate the role of Integrin ⍺11, a collagen binding integrin which preferentially binds to type I collagen, in response to cardiac injury. Fibroblast conditional ⍺11 knockout (KO) mice demonstrated similar cardiac function to that of Wildtype littermates (WT). However, interstitial collagen I (P<0.05) and III (P<0.0001) content was reduce along with cardiac myocyte size (P<0.0001). In response to ligation of the left anterior descending aorta ⍺11 KO mice had significantly increased Infarct size 24 hours post MI (WT=39%, ⍺11KO=64% P<0.05). Larger MI’s resulted in increased mortality in ⍺11 KO mice (22% v’s 57%, P<0.05) due to rupture. Cardiac function 2 days following MI measured by echo demonstrated that Fractional Area Change (FAC) (23% ±1.812 v’s 16%±2.311, P<0.05) and Cardiac Output (8.53ml±1.045 v’s 4.98ml±0.67, P<0.05) were significantly worse in ⍺11 KO compared to WT mice. In the later remodelling response 4 weeks post MI, FAC was again significantly worse for ⍺11 KO mice (~9% ±1.659%, P<0.0001) compared to WT (~19% ± 0.9810%). Moreover, ⍺11 KO mice that survived MI had significantly more collagen I (P<0.0001) content in the remote, peri-infarct and infarct zone’s than that of WT along with, a lack of hypertrophic response. In conclusion, the loss ⍺11 results in increased ventricular dilation, impairs cardiac function and, was associated with increased mortality due to rupture following MI. In mice which survived MI ⍺11 deletion led to increased CF and blunted cardiac myocyte hypertrophy.