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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. Electronic supplementary material The online version of this article (doi:10.1007/s00109-008-0385-4) contains supplementary material, which is available to authorized users.

We and others found sex differences in physiological myocardial hypertrophy (MH) in mice subjected to voluntary cage-wheel running (VCR) and forced exercise training. Female mice showed significantly more MH, suggesting the involvement of estrogen (E2) and estrogen receptors (ER). We therefore investigated the underlying mechanisms leading to sex differences in physiological MH and the role of E2 and ER beta (ERß). Male and female C57/Bl6 wild-type (WT) and ERß-deficient mice (ERß-/-) at the age of 12 weeks performed 8 weeks of VCR or were kept sedentary (sed). Exercise performance was monitored daily and left ventricular mass (LVM) was examined by echocardiography. RNA and protein were analyzed by Real-Time PCR and western blot. Luciferase-reporter Assays were performed with PGC-1a-, MEF2A- and MEF2C-promoter deletion constructs in a human cardiac myocyte cell line (AC16 cells) with/without E2 treatment. Female WT-mice run more than their male counterparts (6.7km/day vs. 4.2km/day; p