Alterations in sodium flux (I) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel Na1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1).
View Article and Find Full Text PDFPhysiological cardiac hypertrophy, in response to stimuli such as exercise, is considered adaptive and beneficial. In contrast, pathological cardiac hypertrophy that arises in response to pathological stimuli such as unrestrained high blood pressure and oxidative or metabolic stress is maladaptive and may precede heart failure. We found that the transcript encoding DNA damage-inducible transcript 4-like (DDiT4L) was expressed in murine models of pathological cardiac hypertrophy but not in those of physiological cardiac hypertrophy.
View Article and Find Full Text PDFBackground: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications.
View Article and Find Full Text PDFBackground: Glutathione peroxidase-3 (GPx-3) is a selenocysteine-containing plasma protein that scavenges reactive oxygen species in the extracellular compartment. A deficiency of this enzyme has been associated with platelet-dependent thrombosis, and a promoter haplotype with reduced function has been associated with stroke risk.
Methods And Results: We recently developed a genetic mouse model to assess platelet function and thrombosis in the setting of GPx-3 deficiency.
J Cardiovasc Pharmacol
May 2011
Interspersed between cardiac myocytes, cardiac fibroblasts serve mainly as a structural support during ventricular wall thickening from embryogenesis until adulthood. Cardiac fibroblasts, however, may also serve as a source of mitogens, extracellular matrix proteins, cytokines, and growth factors that could affect the phenotype of the cardiac myocyte. The crosstalk between cardiac fibroblasts and myocytes is important during cardiac development and remodeling in response to injury.
View Article and Find Full Text PDFPlasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon as a selenocysteine codon and requires signals in the 3'-untranslated region (UTR), including a selenocysteine insertion sequence (SECIS), as well as specific translational cofactors. To ascertain regulatory determinants of GPx-3 expression and function, we generated recombinant GPx-3 (rGPX-3) constructs with various 3'-UTR, as well as a Sec73Cys mutant.
View Article and Find Full Text PDFThe oxidizing nature of the extracellular environment is vastly different from the highly reducing nature of the intracellular compartment. The redox potential of the cytosolic compartment of the intracellular environment limits disulfide bond formation, whereas the oxidizing extracellular environment contains proteins rich in disulfide bonds. If not for an extracellular antioxidant system to eliminate reactive oxygen and nitrogen species, lipid peroxidation and protein oxidation would become excessive, resulting in cellular damage.
View Article and Find Full Text PDFBackground And Purpose: Plasma glutathione peroxidase (GPx-3)-deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences.
Methods: We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender-matched controls by single-stranded conformational polymorphism and sequencing analysis.