Citations

Abstract The aim of this study was to examine the role of HDL subparticles with apolipoprotein (apo) A-I alone (LpA-I) and with apoA-I and apoA-II (LpA-I/A-II) in predicting coronary artery disease. Concentrations of these HDL subparticles were compared in 184 subjects with angiographically confirmed significant coronary artery disease (>50% stenosis of at least one vessel) and 191 age- and sex-matched control subjects without clinical coronary artery disease. LpA-I and LpA-I/A-II were measured with magnetic beads coated with anti–apoA-II antibodies to separate particles containing apoA-II from plasma. Total plasma cholesterol and triglyceride levels were similar in both groups. Although subjects with coronary artery disease had lower HDL cholesterol, plasma apoA-I, LpA-I, and LpA-I/A-II than age- and sex-matched control subjects without coronary artery disease, plasma apoA-I was the best predictor of coronary artery disease. In conclusion, LpA-I and LpA-I/A-II are lower in subjects with coronary artery disease but do not add to plasma apoA-I in predicting the presence of coronary artery disease.

Hypoxia during exercise augments blood flow in active muscles to maintain the delivery of O2 at normoxic levels. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is not completely understood. Therefore, we tested the hypothesis that the hyperemic response to forearm exercise during hyperbaric hyperoxia would be blunted compared with exercise during normoxia. Seven subjects (6 men/1 woman; 25 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; in ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from FBF and blood pressure (in mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 atmospheres absolute (ATA) (sea level) while breathing normoxic gas [21% O2, 1 ATA; inspired Po2 (PiO2) ≈ 150 mmHg] and at 2.82 ATA while breathing hyperbaric normoxic (7.4% O2, 2.82 ATA, PiO2 ≈ 150 mmHg) and hyperoxic (100% O2, 2.82 ATA, PiO2 ≈ 2,100 mmHg) gas. Resting FBF and FVC were less during hyperbaric hyperoxia compared with hyperbaric normoxia ( P < 0.05). The change in FBF and FVC (Δ from rest) during exercise under normoxia (204 ± 29 ml/min and 229 ± 37 ml·min−1·100 mmHg−1, respectively) and hyperbaric normoxia (203 ± 28 ml/min and 217 ± 35 ml·min−1·100 mmHg−1, respectively) did not differ ( P = 0.66–0.99). However, the ΔFBF (166 ± 21 ml/min) and ΔFVC (163 ± 23 ml·min−1·100 mmHg−1) during hyperbaric hyperoxia were substantially attenuated compared with other conditions ( P < 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia.

Abstract Dendritic cells (DCs) are professional APCs that reside in peripheral tissues and survey the body for pathogens. Upon activation by inflammatory signals, DCs undergo a maturation process and migrate to lymphoid organs, where they present pathogen-derived Ags to T cells. DC migration depends on tight regulation of the actin cytoskeleton to permit rapid adaptation to environmental cues. We investigated the role of hematopoietic lineage cell-specific protein 1 (HS1), the hematopoietic homolog of cortactin, in regulating the actin cytoskeleton of murine DCs. HS1 localized to lamellipodial protrusions and podosomes, actin-rich structures associated with adhesion and migration. DCs from HS1−/− mice showed aberrant lamellipodial dynamics. Moreover, although these cells formed recognizable podosomes, their podosome arrays were loosely packed and improperly localized within the cell. HS1 interacts with Wiskott–Aldrich syndrome protein (WASp), another key actin-regulatory protein, through mutual binding to WASp-interacting protein. Comparative analysis of DCs deficient for HS1, WASp or both proteins revealed unique roles for these proteins in regulating podosomes with WASp being essential for podosome formation and with HS1 ensuring efficient array organization. WASp recruitment to podosome cores was independent of HS1, whereas HS1 recruitment required Src homology 3 domain-dependent interactions with the WASp/WASp-interacting protein heterodimer. In migration assays, the phenotypes of HS1- and WASp-deficient DCs were related, but distinct. WASp−/y DCs migrating in a chemokine gradient showed a large decrease in velocity and diminished directional persistence. In contrast, HS1−/− DCs migrated faster than wild-type cells, but directional persistence was significantly reduced. These studies show that HS1 functions in concert with WASp to fine-tune DC cytoarchitecture and direct cell migration.