EPAC1 promotes adaptive responses in human arterial endothelial cells subjected to low levels of laminar fluid shear stress: Implications in flow-related endothelial dysfunction.

Blood flow-associated fluid shear stress (FSS) dynamically regulates the endothelium's ability to control arterial structure and function. While arterial endothelial cells (AEC) subjected to high levels of laminar FSS express a phenotype resistant to vascular insults, those exposed to low levels of laminar FSS, or to the FSS associated with oscillatory blood flow, are less resilient. Despite numerous reports highlighting how the cAMP-signaling system controls proliferation, migration and permeability of human AECs (HAECs), its role in coordinating HAEC responses to FSS has received scant attention.

Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling.

Although cAMP-signalling regulates numerous functions of vascular endothelial cells (VECs), including their ability to impact vascular resistance in response to changes in blood flow dynamics, few of the mechanisms underlying these effects have yet to be described. In addition to forming stable adherens junctions (AJs) in static VEC cultures, VE-cadherin (VECAD) has emerged as a critical component in a key mechanosensor responsible for linking altered blood flow dynamics and the VEC-mediated control of vascular resistance. Previously, a cAMP phosphodiesterase, PDE4D, was shown to coordinate the VEC permeability limiting effects of cAMP-elevating agents in human arterial VECs (HAECs).

Retention of functional genes for S19 ribosomal protein in both the mitochondrion and nucleus for over 60 million years.

Ribosomal protein genes occasionally undergo successful migration from the mitochondrion to the nucleus in flowering plants and we previously presented evidence that the S19 ribosomal protein gene (rps19) had been transferred to the nucleus in the common ancestor of Poaceae grasses. In many lineages, the mitochondrial copy was subsequently lost or pseudogenized, although in rice it was retained and the nuclear copy lost. We have now determined that functional rps19 genes are present in both the mitochondrion and nucleus in brome grass (Bromus inermis).

Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals.

The cyclic nucleotide second messengers cAMP and cGMP each affect virtually all cellular processes. Although these hydrophilic small molecules readily diffuse throughout cells, it is remarkable that their ability to activate their multiple intracellular effectors is spatially and temporally selective. Studies have identified a critical role for compartmentation of the enzymes which hydrolyse and metabolically inactivate these second messengers, the PDEs (cyclic nucleotide phosphodiesterases), in this specificity.

Differential roles of endothelin-1 in angiotensin II-induced atherosclerosis and aortic aneurysms in apolipoprotein E-null mice.

Because both endothelin-1 (ET-1) and angiotensin II (AngII) are independent mediators of arterial remodeling, we sought to determine the role of ET receptor inhibition in AngII-accelerated atherosclerosis and aortic aneurysm formation. We administered saline or AngII and/or bosentan, an endothelin receptor antagonist (ERA) for 7, 14, or 28 days to 6-week- and 6-month-old apolipoprotein E-knockout mice. AngII treatment increased aortic atherosclerosis, which was reduced by ERA.

Cyclic AMP phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a vascular endothelial cadherin (VE-Cad)-based signaling complex and controls cAMP-mediated vascular permeability.

Vascular endothelial cell (VEC) permeability is largely dependent on the integrity of vascular endothelial cadherin (VE-cadherin or VE-Cad)-based intercellular adhesions. Activators of protein kinase A (PKA) or of exchange protein activated by cAMP (EPAC) reduce VEC permeability largely by stabilizing VE-Cad-based intercellular adhesions. Currently, little is known concerning the nature and composition of the signaling complexes that allow PKA or EPAC to regulate VE-Cad-based structures and through these actions control permeability.

Phylogenetic analysis of WNV in North American blood donors during the 2003-2004 epidemic seasons.

West Nile Virus (WNV) collected from 179 human blood donors in 25 US states and three Canadian provinces during the 2003 and 2004 epidemic seasons were genetically analyzed. The evolution of WNV during its Western spread was examined by envelope (E) gene sequencing of all 179 cases and full open reading frame sequencing of a subset of 20 WNV to determine if geographic and temporal segregation of distinct viral variants had occurred. Median joining network analysis was used to examine the genetic relationship between E gene variants and identified four large genetic clusters showing the gradual accumulation of mutations during the virus' western expansion.