Significance: Recent clinical evidence identified anemia to be correlated with severe complications of cardiovascular disease (CVD) such as bleeding, thromboembolic events, stroke, hypertension, arrhythmias, and inflammation, particularly in elderly patients. The underlying mechanisms of these complications are largely unidentified.Recent Advances: Previously, red blood cells (RBCs) were considered exclusively as transporters of oxygen and nutrients to the tissues. More recent experimental evidence indicates that RBCs are important interorgan communication systems with additional functions, including participation in control of systemic nitric oxide metabolism, redox regulation, blood rheology, and viscosity. In this article, we aim to revise and discuss the potential impact of these noncanonical functions of RBCs and their dysfunction in the cardiovascular system and in anemia.Critical Issues: The mechanistic links between changes of RBC functional properties and cardiovascular complications related to anemia have not been untangled so far.Future Directions: To allow a better understanding of the complications associated with anemia in CVD, basic and translational science studies should be focused on identifying the role of noncanonical functions of RBCs in the cardiovascular system and on defining intrinsic and/or systemic dysfunction of RBCs in anemia and its relationship to CVD both in animal models and clinical settings. Antioxid. Redox Signal. 26, 718–742.

Rapid generation of O 2 Ϫ and H 2 O 2 , which is reminiscent of the oxidative burst in neutrophils, is a central component of the resistance response of plants to pathogen challenge. Here, we report that the Arabidopsis rbohA ( for respiratory burst oxidase homolog A ) gene encodes a putative 108-kD protein, with a C-terminal region that shows pronounced similarity to the 69-kD apoprotein of the gp91 phox subunit of the neutrophil respiratory burst NADPH oxidase. The RbohA protein has a large hydrophilic N-terminal domain that is not present in gp91 phox . This domain contains two Ca 2 ϩ binding EF hand motifs and has extended similarity to the human RanGTPase-activating protein 1. rbohA , which is a member of a divergent gene family, generates transcripts of 3.6 and 4.0 kb that differ only in their polyadenylation sites. rbohA transcripts are most abundant in roots, with weaker expression in aerial organs and seedlings. Antibodies raised against a peptide near the RbohA C terminus detected a 105-kD protein that, unlike gp91 phox , does not appear to be highly glycosylated. Cell fractionation, two-phase partitioning, and detergent extraction indicate that RbohA is an intrinsic plasma membrane protein. We propose that plants have a plasma membrane enzyme similar to the neutrophil NADPH oxidase but with novel potential regulatory mechanisms for Ca 2 ϩ and G protein stimulation of O 2 Ϫ and H 2 O 2 production at the cell surface. INTRODUCTIONRecognition of avirulent pathogens causes a burst of oxidative metabolism generating superoxide (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ) (Baker and Orlandi, 1995). Reactive oxygen intermediates are direct protective agents and also drive cross-linking of the cell wall before the activation of transcription-dependent defenses (Lamb and Dixon, 1997). Moreover, the oxidative burst can trigger the collapse of challenged host cells at the onset of the hypersensitive response and generate signals for defense gene induction (Levine et al., 1994; Jabs et al., 1997).The kinetics and defense functions of O 2 Ϫ and H 2 O 2 generation are reminiscent of the oxidative burst during neutrophil activation ( Tenhaken et al., 1995;Lamb and Dixon, 1997). The neutrophil oxidative burst involves the reaction O 2 ϩ NADPH → O 2 Ϫ ϩ NADP ϩ ϩ H ϩ catalyzed by a plasma membrane oxidase, followed by dismutation of O 2 Ϫ to H 2 O 2 (Taylor et al., 1993). The NADPH oxidase consists of two plasma membrane proteins, gp91 phox and p22 phox ( phox for phagocyte oxidase), which together form heterodimeric flavocytochrome b Ϫ 558 and three cytosolic regulatory proteins, p40 phox , p47 phox , and p67 phox , which translocate to the plasma membrane after stimulation to form the active complex (Bokoch, 1994). The small cytosolic GTPase Rac2 and possibly other G proteins also appear to be required for activation of the oxidase.A membrane-bound enzyme resembling the neutrophil NADPH oxidase may contribute to the pathogen-induced oxidative burst in plants. Thus, O 2 Ϫ generation can be observed in microsomal preparat...

Polyelectrolyte multilayer films were employed to support attachment of cultured rat aortic smooth muscle A7r5 cells. Like smooth muscle cells in vivo, cultured A7r5 cells are capable of converting between a nonmotile "contractile" phenotype and a motile "synthetic" phenotype. Polyelectrolyte films were designed to examine the effect of surface charge and hydrophobicity on cell adhesion, morphology, and motility. The hydrophobic nature and surface charge of different polyelectrolyte films significantly affected A7r5 cell attachment and spreading. In general, hydrophobic polyelectrolyte film surfaces, regardless of formal charge, were found to be more cytophilic than hydrophilic surfaces. On the most hydrophobic surfaces, the A7r5 cells adhered, spread, and exhibited little indication of motility, whereas on the most hydrophilic surfaces, the cells adhered poorly if at all and when present on the surface displayed characteristics of being highly motile. The two surfaces that minimized cell adhesion consisted of two varieties of a diblock copolymer containing hydrophilic poly(ethylene oxide) and a copolymer bearing a zwitterionic group AEDAPS, (3-[2-(acrylamido)-ethyldimethyl ammonio] propane sulfonate). Increasing the proportion of AEDAPS in the copolymer decreased the adhesion of cells to the surface. Cells presented with micropatterns of cytophilic and cytophobic surfaces generated by polymer-on-polymer stamping displayed a surface-dependent cytoskeletal organization and a dramatic preference for adhesion to, and spreading on, the cytophilic surface, demonstrating the utility of polyelectrolyte films in manipulating smooth muscle cell adhesion and behavior.

Nontraumatic osteonecrosis continues to be a challenging problem causing debilitating major joint diseases. The etiology is multifactorial, but steroid- and alcohol-induced osteonecrosis contribute to more than two thirds of all cases with genetic risk factors playing an important role in many other cases, especially when they contribute to hypercoagulable states. While the exact mechanisms remain elusive, many new insights have emerged from research in the last decade that have given us a clearer picture of the pathogenesis of nontraumatic osteonecrosis of the femoral head. Progression to end stage osteonecrosis of the femoral head appears to be related to four main factors: interactions involving the differentiation pathway of osteoprogenitor cells that promote adipogenesis, decreased angiogenesis, direct suppression of osteogenic gene expression and proliferation of bone marrow stem cells, and genetic anomalies or other diseases that promote hypercoagulable states.