Catalysis of S-nitrosothiols formation by serum albumin: the mechanism and implication in vascular control

Nitric oxide (NO(.)) is a short-lived physiological messenger. Its various biological activities can be preserved in a more stable form of S-nitrosothiols (RS-NO). Here we demonstrate that at physiological NO(.) concentrations, plasma albumin becomes saturated with NO(.) and accelerates formation of low-molecular-weight (LMW) RS-NO in vitro and in vivo. The mechanism involves micellar catalysis of NO(.) oxidation in the albumin hydrophobic core and specific transfer of NO(+) to LMW thiols. Albumin-mediated S-nitrosylation and its vasodilatory effect directly depend on the concentration of circulating LMW thiols. Results suggest that the hydrophobic phase formed by albumin serves as a major reservoir of NO(.) and its reactive oxides and controls the dynamics of NO(.)-dependant processes in the vasculature.     

The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

Presenilins (PSs) are required for Notch signaling in the development of vertebrates and invertebrates. Mutations in human PS1 and PS2 homologs are a cause of familial Alzheimer's disease (AD). The function of the recently identified ancient family of IMPAS proteins (IMP/SPP/PSH) homologous to PSs is not yet known. We show here that, unlike PSs, IMPs (orthologous C. elegans Ce-imp-2 and human hIMP1/SPP) do not promote Notch (C. elegans lin-12,glp-1) proteolysis or signaling. The knock-down of Ce-imp-2 leads to embryonic death and an abnormal molting phenotype in Caenorhabditis elegans. The molting defect induced by Ce-imp-2 deficiency was mimicked by depleting cholesterol or disrupting Ce-lrp-1 and suppressed, in part, by expression of the Ce-lrp-1 derivate. C. elegans lrp-1 is a homolog of mammalian megalin, lipoprotein receptor-related protein (LRP) receptors essential for cholesterol and lipoprotein endocytosis and signaling. These data suggest that IMPs are functionally distinct from related PSs and implicate IMPs as critical regulators of development that may potentially interact with the lipid-lipoprotein receptor-mediated pathway.     

Ionic mechanisms underlying region-specific remodeling of rabbit atrial action potentials caused by intermittent burst stimulation.

BACKGROUND: Pulmonary veins (PVs) and the coronary sinus (CS) play pivotal roles in triggering some episodes of atrial fibrillation. In isolated rabbit right or left atrial preparations, a 3-hour intermittent burst pacing protocol shortens action potential duration (APD) in CS and PV, but not in sinus node (SN) and left Bachmann bundle (BB) regions. OBJECTIVE: The purpose of this study was to use patch clamp techniques to study the rapidly inactivating (I(to)) and sustained (I(sus)) K(+) currents as well as Ca(2+) currents (I(Ca)) in cells dispersed from intermittent burst pacing and sham PV, BB, CS, and SN regions to determine whether changes in these currents contributed to APD shortening. METHODS: Real-time polymerase chain reaction was performed for transient outward K(+) and Ca(2+) channel subunit mRNAs to determine if intermittent burst pacing affected expression levels. RESULTS: I(to) densities were unaffected by intermittent burst pacing in PV and Bachmann bundle cells. mRNA levels of K(V)4.3, K(V)4.2, K(V)1.4, and KChIP2 subunits of I(to) in both regions were stable. In CS cells, I(to) densities in intermittent burst pacing were greater than in sham (P <.05), but there were no parallel mRNA changes. I(Ca) density of PV cells was reduced from 14.27 +/- 2.08 pA/pF (at -5 mV) in sham to 7.52 +/- 1.65 pA/pF in intermittent burst pacing PV cells (P <.05) due to a significant shift in voltage dependence of activation. These results were seen in the absence of mRNA changes in alpha(1C) and alpha(1D) Ca(2+) channel subunits. In contrast, intermittent burst pacing had no effect on Ca(2+) current densities and kinetics of CS cells, but decreased alpha(1)C and alpha(1)D mRNA levels. CONCLUSION: There is region-specific remodeling of I(to) and I(Ca) by intermittent burst pacing protocols in rabbit atrium. Increased I(to) in CS cells could account for the APD shortening observed with intermittent burst pacing, whereas an intermittent burst pacing-induced shift in voltage dependence of activation may contribute to APD shortening in PV cells.     

Successful lung donation at the age of 6 weeks: Challenges and lessons learned

A clinical case of successful procurement and transplantation of bilateral lungs from 6‐week‐old infant with sepsis secondary to bacterial meningitis is reported. Forty‐one‐day‐old male infant (height 60 cm, weight 4 kg) died of cerebral edema secondary to Escherichia coli meningitis and bacteremia. Preretrieval assessment included the following: arterial gases; pO₂ 50.4 kPa (378 mm Hg), pCO₂ 4.9 kPa (37 mm Hg), on FiO₂ 100%, PEEP 5 cm H₂O. Fiberoptic bronchoscopy showed no secretions nor mucosal inflammation; CXR revealed clear lung fields and pleural spaces. Inspection revealed dense adhesions in pericardial cavity and purulent left hemithorax effusion (urgent Gram‐stain came back as negative) but there was no consolidation in the lung. Good compliance of the lungs on inflation/deflation test was observed. The lungs were retrieved using the technique described. The recipient was a 4‐month‐old infant with alveolar capillary dysplasia and malaligned pulmonary veins. Implantation of the lungs was performed via bilateral thoracosternotomy on cardiopulmonary bypass, cooling to 30°C. Elective support with nitric oxide was used postoperatively. Two years after the transplantation, the recipient doing well with normal lung function. Lung procurement from a 6‐week donor with infectious complications and prolonged ventilation is a challenging undertaking but can be successful and should be attempted whenever possible given the paucity of organs available for pediatric recipients.