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Pharmacological Inhibition of p38/MAPK Improves Cardiac Function in Cardiac‐specific Bag3‐P209L Transgenic Mice
Author(s) -
Eaton Samuel C.,
Takayama Shinuchi,
Sidorova Tatia.,
Murray Katherine T.,
Willis Monte S.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.306.5
Subject(s) - proteotoxicity , bag3 , heart failure , medicine , cardiac function curve , ejection fraction , cardiac fibrosis , cardiomyopathy , genetically modified mouse , endocrinology , transgene , cardiology , biology , microbiology and biotechnology , autophagy , protein aggregation , apoptosis , biochemistry , gene
Bag3 (Bcl‐2‐associated athanogene‐3) is a small heat shock protein expressed predominantly in cardiac and skeletal muscle that regulates proteasomal and autophagosomal protein elimination pathways. Several mutations in Bag3, including a P209L mutation, result in childhood myopathy leading to heart failure. However, the mechanisms by which Bag3 contribute to the pathophysiology of heart failure remain unclear. We recently created cardiac‐specific (alphaMHC) Bag3‐P209L transgenic mice and identified, by conscious echocardiography, a progressive systolic and diastolic heart failure phenotype starting at 8 months of age. We hypothesized that proteotoxicity resulting from misfolded Bag3‐P209L protein contributes to this progressive heart failure phenotype. We first identified increased levels of pre‐amyloid oligomers in Bag3‐P209L mice by immunohistochemistry at one year. Since p38/MAPK signaling is a known regulator of proteotoxicity in neurodegenerative disorders, such as Alzheimer's disease, we next investigated p38 activation in Bag3‐P209L cardiac tissue by immunoblot. At one year, Bag3‐P209L hearts have increased activation of p38 compared to age matched wildtype hearts(p<0.05). To test p38 as a clinically relevant target in Bag3‐P209L heart failure, we treated Bag3‐P209L mice daily with the p38 inhibitor SB203580 (1 mg/kg bw). Conscious echocardiography of treated Bag3‐P209L (n=4) and wildtype (n=4) mice revealed a reversal of systolic heart failure (ejection fraction) by 10 days post‐injection, indicating a role of p38 signaling in Bag3‐P209L cardiomyopathy. Future studies will focus on the biochemical effects of SB203580 treatment to elucidate the therapeutic mechanism of p38 inhibition in Bag3‐P209L mice. This study provides a novel therapeutic target for human Bag3‐mutation related cardiomyopathy where no therapy currently exists.