Sex-specific pathways in early cardiac response to pressure overload in mice

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2008-09, Vol.86 (9), p.1013-1024
• Main Authors: Witt, Henning, Schubert, Carola, Jaekel, Juliane, Fliegner, Daniela, Penkalla, Adam, Tiemann, Klaus, Stypmann, Joerg, Roepcke, Stefan, Brokat, Sebastian, Mahmoodzadeh, Shokoufeh, Brozova, Eva, Davidson, Mercy M., Ruiz Noppinger, Patricia, Grohé, Christian, Regitz-Zagrosek, Vera
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood Pressure; Cardiomegaly - etiology; Cardiomegaly - pathology; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; General aspects; Heart Failure - etiology; Heart Failure - pathology; Heart Ventricles - anatomy & histology; Heart Ventricles - pathology; Hemodynamics; Human Genetics; Internal Medicine; Male; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Medicine; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Original; Original Article; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Sex Characteristics; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors; Ventricular Function, Left
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-008-0385-4

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 (α-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 TGFβ2, 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.