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

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.

NHR-40, a Caenorhabditis elegans supplementary nuclear receptor, regulates embryonic and early larval development.

Nuclear hormone receptors (NHRs) are important regulators of development and metabolism in animal species. They are characterized by the ability to regulate gene expression in response to the binding of small hydrophobic molecules, hormones, metabolites, and xenobiotics. The Caenorhabditis elegans genome contains 284 sequences that share homology to vertebrate and insect NHRs, a surprisingly large number compared with other species. The majority of C. elegans NHRs are nematode-specific and are referred to as supplementary nuclear receptors (supnrs) that are thought to have originated by duplications of an ancient homolog of vertebrate HNF4. Here, we report on the function of NHR-40, a member of a subgroup of 18 Caenorhabditis elegans supnrs that share DNA-binding domain sequence CNGCKT. NHR-40 is expressed from at least two promoters, generates at least three transcripts, and is detectable in pharyngeal, body wall, and sex muscles as well as in a subset of neurons. The downregulation of nhr-40 by RNAi, or a mutant with an intronic region deletion, results in late embryonic and early larval arrest with defects in elongation and morphogenesis. The nhr-40 loss of function phenotype includes irregular development of body wall muscle cells and impaired movement and coordination resembling neuromuscular affection. NHR-40 joins the list of C. elegans NHRs that regulate development and suggests that members of extensive nematode supnr family have acquired varied and novel functions during evolution.