In addition to sperm-related genes, the male-specific chromosome Y (chrY) contains a class of ubiquitously expressed and evolutionary conserved dosage-sensitive regulator genes that include the ...neighboring Uty, Ddx3y and (in mice) Eif2s3y genes. However, no study to date has investigated the functional impact of targeted mutations of any of these genes within adult non-reproductive somatic cells. We thus compared adult male mice carrying a gene trap within their Uty gene (Uty
) to their wild-type (WT) isogenic controls, and performed deep sequencing of RNA and genome-wide profiling of chromatin features in extracts from either cardiac tissue, cardiomyocyte-specific nuclei or purified cardiomyocytes. The apparent impact of Uty
on gene transcription concentrated mostly on chrY genes surrounding the locus of insertion, i.e. Uty, Ddx3y, long non-coding RNAs (lncRNAs) contained within their introns and Eif2s3y, in addition to possible effects on the autosomal Malat1 lncRNA. Notwithstanding, Uty
also caused coordinate changes in the abundance of hundreds of mRNA transcripts related to coherent cell functions, including RNA processing and translation. The results altogether indicated that tightly co-regulated chrY genes had nonetheless more widespread effects on the autosomal transcriptome in adult somatic cells, most likely due to mechanisms other than just transcriptional regulation of corresponding protein-coding genes.
Assessment of cardiac anatomy and function by cardiovascular magnetic resonance (CMR) is accurate and reproducible and is commonly performed to clarify borderline results obtained by other ...techniques. Normal reference values are lacking in a large sample of young healthy adults. As CMR is increasingly solicited to discriminate normality from equivocal disease in this population, we sought to determine reliable reference values.
A sample of 434 Caucasian adults aged 26 ± 4 years (45% male) without cardiovascular disease or risk factors (including obesity and smoking) underwent CMR. Blood pressure, electrocardiogram, and plasma markers (lipid profile, fasting glucose, troponin, and Nt-pro-BNP) were within normal limits and typical of a low-cardiometabolic-risk profile. End-diastolic (ED), end-systolic (ES), and stroke volumes were greater in men for left and right atria and ventricles. Left ventricular (LV) mass was higher in men. ED wall thickness of all segments was greater in men, whereas ES wall thickening (segmental function) was similar in both genders. After normalization to body surface area, all gender differences remained. Left and right ventricular volumes were lower, and left atrial volumes were higher in older individuals. In contrast, LV mass was not associated with age.
This is the first large database of reference ranges for ventricular and atrial functions, volumes, and mass in young Caucasian men and women devoid of cardiovascular disease and risk factors. These data will contribute to improving the accuracy of CMR interpretation for clinical and research applications.
Despite indications that hearts from the C57BL/6N and C57BL/6J mouse substrains differ in terms of their contractility and their responses to stress-induced overload, no information is available ...about the underlying molecular and cellular mechanisms. We tested whether subacute (48 hours) and chronic (14 days) administration of angiotensin II (500 ng/kg per day) had different effects on the left ventricles of male C57BL/6J and C57BL/6N mice. Despite higher blood pressure in C57BL/6J mice, chronic angiotensin II induced fibrosis and increased the left ventricular weight/body weight ratio and cardiac expression of markers of left ventricular hypertrophy to a greater extent in C57BL/6N mice. Subacute angiotensin II affected a greater number of cardiac genes in C57BL/6N than in C57BL/6J mice. Some of the most prominent differences were observed for markers of (1) macrophage activation and M2 polarization, including 2 genes (osteopontin and galectin-3) whose inactivation was reported as sufficient to prevent angiotensin II-induced myocardial fibrosis; and (2) fibroblast activation. These differences were confirmed in macrophage- and fibroblast-enriched populations of cells isolated from the hearts of experimental mice. When testing F2 animals, the amount of connective tissue present after chronic angiotensin II administration did not cosegregate with the inactivation mutation of the nicotinamide nucleotide transhydrogenase gene from C57BL/6J mice, thus discounting its possible contribution to differences in cardiac remodeling. However, expression levels of osteopontin and galectin-3 were cosegregated in hearts from angiotensin II-treated F2 animals and may represent endophenotypes that could facilitate the identification of genetic regulators of the cardiac fibrogenic response to angiotensin II.
Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL) linked in trans to the expression of 190 gene transcripts and in cis to the expression ...of only two genes, one of which was Ypel5. Most of the trans-expression QTL genes were interferon-stimulated genes (ISGs), and their expression in mouse macrophage cell lines was stimulated in an IFNB1-dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE. We thus found that the Ypel5 gene (contained in a locus linked to a network of ISGs in mice) is a negative regulator of IFNB1 production and innate immune responses that interacts functionally and physically with TBK1/IKBKE kinases.
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•One QTL associates in trans with expression of 190 genes in mouse cardiac tissue•Expression levels of the Ypel5 gene associate in cis with that QTL•Ypel5 regulates interferon-responsive genes present in the hotspot of trans-regulated genes•YPEL5 interacts functionally and physically with TBK1/IKBKE kinases
Jeidane et al. find that a locus containing the Ypel5 gene is linked to the expression of interferon-responsive genes in mice. Further examination reveals that the Ypel5 gene is a negative regulator of IFNB1 production and non-conventional IKK kinases.
Most common diseases and/or their consequences, including hypertension and susceptibility to end-organ damage, have genetic components. Contrary to hereditary Mendelian diseases (where the existence ...of a rare mutation within a single gene usually dictates whether signs of the disease are present), the manifestations of common diseases correspond to what is defined in genetics as “quantitative complex traits”. Such traits show within populations continuous variation from low to high values, and are shaped by the interactions of a great number of genes (each typically having small effects on their own) with environmental factors. Consequently, identification of genetic variants contributing to complex traits must rely on methods that are different than those used for the identification of Mendelian genetic mutations (which can be performed by following within pedigrees the hereditary transmission of markers linked to the mutated gene). Among several available tools, genetic animal models have proved particularly useful to identify the effects of naturally occurring genetic variants and their effects within mammalian organisms. Indeed, inbred strains are organisms that carry identical copies of each gene. Accordingly, it is possible by performing crosses between them to reduce the complexity of the problem, since the progeny of crosses will carry only 2 possible variants of any gene and experimental and environmental conditions can be controlled.
Abstract While compelling evidence supports the central role of mitochondrial dysfunction in the pathogenesis of heart failure, there is comparatively less information available on mitochondrial ...alterations that occur prior to failure. Building on our recent work with the dystrophin-deficient mdx mouse heart, this review focuses on how early changes in mitochondrial functional phenotype occur prior to overt cardiomyopathy and may be a determinant for the development of adverse cardiac remodelling leading to failure. These include alterations in energy substrate utilization and signalling of cell death through increased permeability of mitochondrial membranes, which may result from abnormal calcium handling, and production of reactive oxygen species. Furthermore, we will discuss evidence supporting the notion that these alterations in the dystrophin-deficient heart may represent an early “subclinical” signature of a defective nitric oxide/cGMP signalling pathway, as well as the potential benefit of mitochondria-targeted therapies. While the mdx mouse is an animal model of Duchenne muscular dystrophy (DMD), changes in the structural integrity of dystrophin, the mutated cytoskeletal protein responsible for DMD, have also recently been implicated as a common mechanism for contractile dysfunction in heart failure. In fact, altogether our findings support a critical role for dystrophin in maintaining optimal coupling between metabolism and contraction in the heart.
Congestive heart failure (CHF) is a disease that is characterized by progressive left ventricular (LV) dysfunction and dilatation. Oxidative stress is thought to contribute to the progression of CHF, ...and antioxidants have been shown to have beneficial effects when started early after myocardial infarction (MI). In this study, we tested whether the powerful antioxidant probucol would attenuate progression of CHF once it was established after MI in the rat.
Ligation of a coronary artery was used to create an MI in rats (n=266). Survivors were then randomized 20 days after MI to either probucol 61 mg. kg(-1). d(-1) or vehicle and followed up for a total of 100 days after MI. Studies of cardiac hemodynamics, LV remodeling, cardiac apoptosis and morphology, systemic neurohumoral activation, oxidative stress, and renal function were then evaluated. Probucol improved LV function (LV maximum rate of pressure rise from 3103 to 4250 mm Hg/s, P<0.05, and LV end-diastolic pressure decrease from 28 to 24 mm Hg, P<0.05), reduced pulmonary weights, prevented right ventricular systolic hypertension, and preserved renal function compared with vehicle. Probucol also prevented LV dilatation, prevented wall thinning (1.70 versus 1.42 mm, P<0.05), reduced cardiac fibrosis and cardiac apoptosis, attenuated increased myocardial cell cross-sectional area, and increased scar thickness.
In chronic CHF, probucol exerts multiple beneficial morphological effects that result in better LV remodeling and function, reduced neurohumoral activation, and preserved renal function.
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