Inhibiting Fibronectin Improves Cardiac Function in a Mouse Model of Heart Failure
Authors: Alandi Inigo Valiente , Nieman Michelle , Molkentin Jeffery D. , Blaxall Burns C. 
Published: November 2023

Hypothesis

Heart failure (HF) is a devastating disease with poor prognosis. Hallmarks of HF include pathologic chamber remodeling, gradual interstitial fibrosis, and reduced ventricular function. In response to cardiac injury, cardiac fibroblasts (CF) undergo pathologic transition to a myofibroblast (MF) phenotype, characterized by excess production of collagen and other myocardial extracellular matrix (ECM) components, thus exacerbating HF. The ECM protein fibronectin (FN) plays an essential role in pathologic remodeling in HF. FN polymerization tightly regulates the assembly of collagens; it also promotes cell proliferation, growth, migration and contractility. We hypothesize that inhibiting FN polymerization utilizing small peptides or ablating FN gene expression with inducible, activated fibroblast‐restricted FN‐knockout (KO) mice will attenuate cardiac remodeling by limiting pathologic CF activation and interstitial fibrosis.

Objective

Determine the efficacy and specificity of FN inhibition or CF‐restricted ablation in attenuating the progression of HF; determine the mechanism(s) of FN inhibition in attenuating CF activation by exploring the effects on downstream signaling in primary mouse CF. We aim to reduce pathologic remodeling after cardiac injury through targeting fibronectin expression and polymerization.

Methods and Results

To investigate this hypothesis, we first administered daily injections of the FN polymerization inhibitory peptide pUR4 into wild‐type animals after ischemia‐reperfusion (IR) injury for 1 week. Mice receiving pUR4 demonstrated significant improvement in cardiac function compared to control peptide‐treated animals. In addition, pUR4‐treated animals showed a robust reduction of fibrosis, inflammatory cell infiltration, pro‐inflammatory cytokines, apoptosis and hypertrophy. CF isolated from homeostatic hearts and treated with pUR4 confirmed a reduction in cell migration with no effect on cell adhesion or proliferation. However, activated CF from injured hearts treated with pUR4 showed an impaired ability to proliferate and migrate. To further examine the therapeutic efficacy and specificity of pUR4 in the improvement of cardiac function and reduction of cardiac fibrosis, we investigated the fibroblast‐mediated role of FN in pathologic cardiac remodeling utilizing our fibroblast‐restricted PeriostinmERCremER;FNFlox/Flox (Periostin‐‐‐FN‐KO). Analysis of cardiac function by echocardiography of Periostin‐FN‐KO 4 weeks post‐IR revealed a promising cardioprotective effect compared to the control group (FNFlox/Flox).

Conclusion

These data suggest that FN inhibition by pUR4 and/or FN genetic ablation in CF may be cardioprotective following cardiac injury, attenuating the pathological effects of FN overproduction in the activated CF after injury. We believe that fibroblast‐restricted Periostin‐FN‐KO mice will synergize with pharmacological pUR4 effects in ameliorating cardiac fibrosis; both models target the activated CF that arise after cardiac injury and will possibly lead to the generation of novel treatments for HF.