Abstract 16974: Augmentation of Vasoactive Intestinal Peptide Signaling Prevents the Development of Duchenne Muscular Dystrophy-Associated Cardiomyopathy Through Inhibition of NF-κB Signaling
| Autor: | Pradeep P.A. Mammen, Yunbeen Bae, John M. Shelton, Bret M. Evers, Jian Huang, Tara C. Tassin, Sue Arnold, Terry Gemelli, John T. Lee, Xuan Jiang |
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| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
business.industry Duchenne muscular dystrophy Vasoactive intestinal peptide Cardiomyopathy Muscle degeneration medicine.disease Nf κb signaling Fibrosis Physiology (medical) Heart failure Cardiac hypertrophy medicine Cancer research Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation. 142 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circ.142.suppl_3.16974 |
| Popis: | Duchenne muscular dystrophy (DMD) is a recessive X-linked neuromuscular disorder characterized by progressive muscle degeneration with DMD-associated cardiomyopathy being the primary mode of death. Vasoactive intestinal peptide (VIP) is a 28 amino acid neuropeptide with biological effects mediated by G protein-coupled receptors. Utilizing a genetically modified form of VIP (PB1046) targeting cardiomyocytes, we hypothesized that augmentation of VIP signaling prevents the development of DMD-associated cardiomyopathy through inhibition of NF-κB. Either PB1046 (1.5 mg/kg) or a Placebo (saline) was injected subcutaneously every other day in three mouse models: DMD mdx:Utr+/- , DMD mdx , and wild type mice starting at 4 weeks of age for a total of 8 weeks. Cardiac function was assessed by weekly echocardiography. The cardiac tissues were collected at 14 weeks of age for histological and molecular analyses. Drug-treated DMD mdx:Utr+/- mice showed preservation of cardiac function (fractional shortening 61%±0.4 vs 45%±1.3, p p mdx:Utr+/- mice was decreased compared with controls (44.6±5.3 vs 64.3±6.9 nmol/100mg heart weight, p mdx:Utr+/- mice as compared to controls (n=3). Western blot analyses revealed increased phosphorylation of CREB (1.97±0.02 vs 1.00±0.06, p p mdx:Utr+/- mice. The molecular mechanism underlying the benefits of VIP signaling suggests an upregulation of cAMP-CREB signaling with downregulation of NF-kB signaling leading to inhibition of inflammation and fibrosis within drug-treated DMD hearts. VIP signaling in DMD may serve as a new therapeutic target for the treatment of DMD-associated cardiomyopathy. |
| Databáze: | OpenAIRE |
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