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The TIMP3/Apelin axis Regulates Atherosclerosis and Heart Metabolism leading to increased mortality in ApoE null Mice

ABSTRACT: The role of TIMP3 in the context of cardiovascular remodeling is relatively unexplored when considering classical risk factors such as hypercholesterolemia, diabetes and hypertension. To learn more the role of TIMP3 in the progression of cardiovascular disease we combined genetics, metabolomics and in vivo phenotypical analysis using the hypercholesterolemic ApoE null mice to generate ApoE-/-Timp3-/- mice, the latter showing increased atherosclerosis, increased mortality and arrhythmias compared to ApoE-/- mice. We have previously described Timp3-/-mice in ( Fiorentino, L., et al., Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. Acta Diabetol, 2013) . To generate ApoE-/-Timp3-/- knockout animals we crossbred the 2 strains. Offsprings were then backcrossed into ApoE animals for 6 generations to generate a pure lineage. Collectively, metabolite profiles, gene and protein expression consistently suggested a role for TIMP3 to underlie a decreased activation of PPARα/AMPK to dampen fatty acids β-oxidation eventually leading to atherosclerotic plaque composition vulnerability and perturbation of heart metabolism. mRNA profiling in ApoE-/-Timp3-/- mice revealed a TIMP3 effect to regulate Apelin, which we found decreased in the circulation due to its specific downregulation at the myocardial level but not in other well known sites of expression such as the adipose tissue. mRNA sequencing of the heart of ApoE-/-Timp3-/- mice vs ApoE-/- littermates controls.

ORGANISM(S): Mus musculus  

SUBMITTER: Stefano Rizza  Stefano Menini   Marina Cardellini   Rossella Menghini   Ivan Arisi   Daniela Carnevale   Giuseppe Lembo   Giuseppe Pugliese   Viviana Casagrande   Alessandro Mauriello   Massimo Federici   Michele Cavalera   Rama Khokha   Antonino Cattaneo   Maria Mavilio   Robert Stoehr    

PROVIDER: E-GEOD-53548 | ArrayExpress | 2015-01-23



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