title: Sex-specific pathways in early cardiac response to pressure overload in mice.
abstract: Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (alpha-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFbeta2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF.
authors.affiliation: Berlin Institute of Gender in Medicine (GiM), Charité-Universitaetsmedizin Berlin, Luisenstrasse 65, 10117 Berlin, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Witt
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.forename: Juliane
authors.initials: J
authors.lastname: Jaekel
authors.forename: Daniela
authors.initials: D
authors.lastname: Fliegner
authors.forename: Adam
authors.initials: A
authors.lastname: Penkalla
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
authors.forename: Joerg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Roepcke
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brokat
authors.forename: Shokoufeh
authors.initials: S
authors.lastname: Mahmoodzadeh
authors.forename: Eva
authors.initials: E
authors.lastname: Brozova
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz Noppinger
authors.forename: Christian
authors.initials: C
authors.lastname: Grohé
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006333:Heart Failure / Q000209:etiology / Q000473:pathology; D006352:Heart Ventricles / Q000033:anatomy & histology / Q000473:pathology; D006439:Hemodynamics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011897:Random Allocation; D012727:Sex Characteristics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D016277:Ventricular Function, Left
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors