Abstract 264: Inhibiting Fibronectin Improves Cardiac Function in a Mouse Model of Heart Failure
| Autor: | Michelle L. Nieman, Iñigo Valiente-Alandi, Burns C. Blaxall |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Circulation Research. 119 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.119.suppl_1.264 |
| Popis: | Heart failure (HF) is a devastating disease with poor prognosis. Hallmarks of HF include pathological fibrosis, remodeling and reduced 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 of the ECM in HF. FN polymerization tightly regulates the assembly of collagens and promotes cell proliferation, growth, migration and contractility. We hypothesize that inhibiting FN polymerization utilizing novel peptides will attenuate cardiac remodeling by limiting CF activation and fibrosis. To investigate this hypothesis, we administered daily injections of the FN polymerization inhibitory peptide pUR4 into wild type animals after ischemia-reperfusion (IR) injury for 1 week, and hearts were harvested 4 weeks post-IR. 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. The information gleaned from the in vitro data obtained from isolated CF, from unchallenged or injured hearts, treated with pUR4 or control peptide suggested attenuation in cell migration and proliferation cell functions. To examine the impact of FN genetic ablation in cardiac function and cardiac fibrosis, we investigated the fibroblast-mediated role of FN in pathologic cardiac remodeling utilizing our fibroblast-restricted Periostin mERCremER ;FN Flox/Flox (Periostin FN-KO). Analysis of cardiac function by echocardiography of Periostin-FN-KO 4 weeks post-IR revealed limited cardioprotective effect compare to the control group (FN Flox/Flox ). This data suggest that inhibiting FN polymerization may be cardioprotective following cardiac injury, attenuating the pathological effects of FN overproduction and polymerization in the activated CF after injury. Limiting FN polymerization will possible lead to the generation of novel treatments for HF. |
| Databáze: | OpenAIRE |
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