袋3
自噬
细胞生物学
细胞凋亡
标记法
心脏纤维化
医学
生物
内科学
心力衰竭
生物化学
作者
Megan T. Quintana,Samuel W. Eaton,Cecelia C. Yates,Shinichi Takayama,Monte S. Willis
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2015-11-10
卷期号:132 (suppl_3)
标识
DOI:10.1161/circ.132.suppl_3.18238
摘要
Introduction: There are 6 members of the Bcl2-related anthanogene (BAG) protein family, which act as co-chaperones expressed at high levels in skeletal and cardiac muscle. BAG3 is involved in chaperone-assisted selective autophagy (CASA). Mutations in the Z-disc protein BAG3 have recently been found to cause myofibrillar myopathy (MFM) with cardiac complications (dilated cardiomyopathy). The missense mutation Pro209Leu (P209L) is one of ten BAG3 mutations identified in human disease to date. Hypothesis: Cardiac BAG3 P209L expression inhibits CASA, evidenced by less autophagic flux of misfolded proteins. Methods: Cardiac specific transgenic mice with alphaMHC-driven human Bag3P209L were created and analyzed functionally over 12 months. Histological analysis of apoptosis (TUNEL), pre-amyloid oligomers (PAO), and fibroblasts were performed in parallel with transmission electron microscopy (TEM) and molecular analysis of autophagy and mitochondrial dynamics. Results: Starting at 8 months, Bag3 P209L Tg+ hearts had significantly depressed systolic function. By 12 months, significant deficits in both diastolic and systolic function were identified, along with increased number of fragmented mitochondria and significant alterations in genes regulating mitochondrial fusion (Opa1) and Fission (Drp1). Immunofluorescence analysis revealed no differences in apoptosis (TUNEL) or autophagic flux (LC3II). But increased levels of cardiomyocyte pre-amyloid oligomers (PAO) were identified by confocal immunofluorescence. As PAO proteotoxic intermediates found in neurodegenerative diseases reportedly activate p38 MAPK, we assayed BAG3 P209L Tg+ hearts and found a significant ~50% increase in phospho-p38/p38. Conclusion: As increased activated p38 activity has negative inotropic and restrictive diastolic effects in vivo, we conclude that inhibiting p38 activity in BAG3 P209L patients may attenuate and/or delay the onset of heart failure. Studies are underway testing this hypothesis using specific inhibitors of P38 and downstream signaling pathways in vivo.
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