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Heterozygous Deletion of Mediator Subunit 1 Causes Heart Failure in Mice
Author(s) -
Spitler Kathryn,
Grueter Chad
Publication year - 2017
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.31.1_supplement.687.10
Subject(s) - mediator , heart failure , biology , gene expression , gene , medicine , endocrinology , genetics
Cardiac gene expression is altered during heart failure, but the mechanisms underlying these transcriptional changes remains unclear. The Mediator complex governs gene transcription by linking upstream cellular signals with transcriptional machinery. Mediator subunit 1 (Med1) plays a pivotal role in regulating gene expression by serving as a transcriptional coactivator for nuclear receptors. Our objective is to elucidate the role for Med1 in cardiac transcriptional regulation. Expression of Med1 in the heart is essential as cardiac deletion of Med1 results in rapid progression into heart failure and death within 2–3 weeks. Given this early lethality during an important developmental time period for the heart, we generated a heterozygous cardiac‐specific deletion of Med1 (cMed1+/−) using the alpha myosin heavy chain expressing cre recombinase bred into Med1 floxed mice. These mice allow us the ability to understand the role of Med1 under more physiological conditions and enables examination into gene expression changes in response to cardiac stresses that lead to heart failure. cMed1+/− resulted in a more gradual lethality phenotype starting at 10 months of age. At one year of age echocardiography, qPCR and Western blot analysis was performed. cMed1+/− male hearts had the expected ~50% reduction in Med1 mRNA and protein levels, resulting in reduced ejection fraction (47% vs. 87%) and increased heart mass (50%) compared to Med1 floxed controls. Transverse sections of cMed1+/− hearts revealed ventricular dilation. Expression of heart failure marker genes ( Nppa , Nppb, and Myh7 ) and pro‐fibrotic genes ( Tgfb2 and Col11a1 ) was increased in hearts from cMed1+/− mice compared to Med1 floxed controls while there was an decrease in the major adult‐associated contractile component Myh6 . Taken together, these data indicate that physiological Med1 levels are essential for cardiac gene expression and function as Med1 haploinsufficiency causes cardiac dysfunction and failure. Support or Funding Information NIH/NHLBI R01 HL125436‐02, Fraternal Order of Eagles Diabetes Research Center, the University of Iowa Carver College of Medicine, and NIH T32 Postdoctoral Fellowship‐5T32HL007121‐38