Integrin alpha 11 is cardioprotective post myocardial infarction, regulating infarct formation and collagen organization
Authors: Meagher P , Lee X , Desjardins J F , Mcculloch C A , Connelly K A 
Published: November 2023

Background

Post Myocardial Infarction (MI), fibrosis and in particular collagen production is an important response in order to replace apoptotic cells within the injured area and stabilize the heart wall1. Cardiac fibroblasts in and around the infarct region under mechanical and biochemical stress transform into myofibroblasts, secreting collagen to help stabilize the infarct segment2. In the short term this is an appropriate response to avoid rupture and death3. However, Long term collagen deposition will increase ventricular stiffness reducing compliance leading to further cardiac dysfunction and heart failure4. Mechanical activation of collagen production and fibrosis is understood to be a significant mediator of cardiac fibrosis, yet the mechanisms controlling mechanical activation of fibrosis are not well understood5,6.

Purpose

Here, we sort to investigate the role of Integrin α11 in cardiac remodelling post MI, a collagen binding integrin which preferentially binds to type I collagen and, is significantly upregulated post MI4,7.

Methods

Fibroblast Conditional α11 knockout (KO) and Wildtype Littermates (WT) underwent either SHAM or left anterior descending aorta (LAD) ligation surgery. Cardiac function was assessed with echocardiography and pressure volume loops. Ventricle samples were processed for FFPE histological/immunohistochemical analysis with hematoxylin/eosin, Collagen I & III antibodies. Finally, Second Harmonic generation microscopy was undertaken to identify collagen organisation with previously validated CurveAlign and CT-Fire algorithms.

Results

α11KO and WT mice demonstrated similar cardiac function. There was evidence of basal structural differences as Collagen I (P&lt;0.05) and III (P&lt;0.0001) deposition was reduced along with cardiac myocyte size (P&lt;0.0001) in α11KO mice. In response to LAD ligation α11KO mice had significantly worse mortality (∼57% v’s ∼22%, P&lt;0.05) which, correlated with an increased MI size (WT=∼39%, α11KO=∼64% P&lt;0.05). Cardiac function 2 days following ligation measured by echo demonstrated that Fractional Area Change (FAC) (23%±2 v’s 16%±2 P&lt;0.05) and Cardiac Output (8.5ml±1 v’s 5ml±0.7, P&lt;0.05) were significantly worse in α11 KO compared to WT mice. The reduced function persisted 4 weeks post ligation as FAC was significantly worse in α11KO mice (∼9%±2%, P&lt;0.0001) compared to WT (∼19%±1%). Moreover, α11KO mice that survived MI had significantly more collagen I (P&lt;0.0001) content in the remote, peri-infarct and infarct zone’s than that of WT along with a lack of hypertrophic response. Finally, Collagen alignment measured using SHG images with CurveAlign demonstrated collagen fibres had significantly less structural alignment in α11KO mice (P&lt;0.05).

Conclusion

We demonstrate a cardioprotective role for Integrin α11 post myocardial infarction. Where, the lack of α11 leads to worsened mortality, larger MI, worsened cardiac function and impaired collagen organisation in the infarct post MI.