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Cardiovascular Phenotypes (cardiovascular + phenotype)
Selected AbstractsThe role of caveolin-1 in cardiovascular regulationACTA PHYSIOLOGICA, Issue 2 2009A. Rahman Abstract Caveolae are omega-shaped membrane invaginations present in essentially all cell types in the cardiovascular system, and numerous functions have been ascribed to these structures. Caveolae formation depends on caveolins, cholesterol and polymerase I and transcript release factor-Cavin (PTRF-Cavin). The current review summarizes and critically discusses the cardiovascular phenotypes reported in caveolin-1-deficient mice. Major changes in the structure and function of heart, lung and blood vessels have been documented, suggesting that caveolae play a critical role at the interface between blood and surrounding tissue. According to an emerging paradigm, many of these changes are secondary to uncoupling of endothelial nitric oxide synthase. Thus, nitric oxide synthase not only synthesizes more nitric oxide in the absence of caveolin-1, but also more superoxide with potential pathogenic consequences. It is further argued that the vasodilating drive from increased nitric oxide production in caveolin-1-deficient mice is balanced by changes in the vascular media that favour increased dynamic resistance regulation. Harnessing the therapeutic opportunities buried in caveolae, while challenging, could expand the arsenal of treatment options in cancer, lung disease and atherosclerosis. [source] Genome-wide association studies of cardiovascular risk factors: design, conduct and interpretationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009J. C. BIS Summary., Relying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium [1]. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes. [source] Cardiovascular abnormalities in Folr1 knockout mice and folate rescue,BIRTH DEFECTS RESEARCH, Issue 4 2007Huiping Zhu Abstract BACKGROUND: Periconceptional folic acid supplementation is widely believed to aid in the prevention of neural tube defects (NTDs), orofacial clefts, and congenital heart defects. Folate-binding proteins or receptors serve to bind folic acid and 5-methyltetrahydrofolate, representing one of the two major mechanisms of cellular folate uptake. METHODS: We herein describe abnormal cardiovascular development in mouse fetuses lacking a functional folate-binding protein gene (Folr1). We also performed a dose-response study with folinic acid and determined the impact of maternal folate supplementation on Folr1 nullizygous cardiac development. RESULTS: Partially rescued preterm Folr1,/, (formerly referred to as Folbp1) fetuses were found to have outflow tract defects, aortic arch artery abnormalities, and isolated dextracardia. Maternal supplementation with folinic acid rescued the embryonic lethality and the observed cardiovascular phenotypes in a dose-dependant manner. Maternal genotype exhibited significant impact on the rescue efficiency, suggesting an important role of in utero folate status in embryonic development. Abnormal heart looping was observed during early development of Folr1,/, embryos partially rescued by maternal folinic acid supplementation. Migration pattern of cardiac neural crest cells, genetic signals in pharyngeal arches, and the secondary heart field were also found to be affected in the mutant embryos. CONCLUSIONS: Our observations suggest that the beneficial effect of folic acid for congenital heart defects might be mediated via its impact on neural crest cells and by gene regulation of signaling pathways involved in the development of the pharyngeal arches and the secondary heart field. Birth Defects Research (Part A) 2007. © 2007 Wiley-Liss, Inc. [source] Cardiovascular and renal phenotyping of genetically modified mice: A challenge for traditional physiologyCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2003Sharyn M Fitzgerald Summary 1.,The advent of techniques to genetically modify experimental animals and produce directed mutations in both a conditional and tissue-specific manner has dramatically opened up new fields for physiologists in cardiovascular and renal research. 2.,A consequence of altering the genetic background of mice is the difficulty in predicting the phenotypic outcome of the genetic mutation. We therefore suggest that physiologists may need to change their current experimental paradigms to face this new era. Hence, our aim is to propose a complementary research philosophy for physiologists working in the post-genomic era. That is, instead of using strictly hypothesis-driven research philosophies, one will have to perform screening studies of mutant mice, within a field of interest, to find valuable phenotypes. Once a relevant phenotype is found, in-depth studies of the underlying mechanisms should be performed. These follow-up studies should be performed using a traditional hypothesis-driven research philosophy. 3.,The rapidly increasing availability of mutated mouse models of human disease also necessitates the development of techniques to characterize these various mouse phenotypes. In particular, the miniaturization and refinement of techniques currently used to study the renal and cardiovascular system in larger animals will be discussed in the present review. Hence, we aim to outline what techniques are currently available and should be present in a laboratory to screen and study renal and cardiovascular phenotypes in genetically modified mice, with particular emphasis on methodologies used in the intact, conscious animal. [source] | |||||||||||||