A key question in hypertension is: How is long-term blood pressure controlled? A clue is that chronic salt retention elevates an endogenous ouabain-like compound (EOLC) and induces salt-dependent hypertension mediated by Na + /Ca 2+ exchange (NCX). The precise mechanism, however, is unresolved. Here we study blood pressure and isolated small arteries of mice with reduced expression of Na + pump α1 (α1 +/-) or α2 (α2 +/-) catalytic subunits. Both low-dose ouabain (1-100 nM; inhibits only α2) and high-dose ouabain (≥1 µM; inhibits α1) elevate myocyte Ca 2+ and constrict arteries from α1 +/-, as well as α2 +/-and wild-type mice. Nevertheless, only mice with reduced α2 Na + pump activity (α2 +/-), and not α1 (α1 +/-), have elevated blood pressure. Also, isolated, pressurized arteries from α2 +/-, but not α1 +/-, have increased myogenic tone. Ouabain antagonists (PST 2238 and canrenone) and NCX blockers (SEA0400 and KB-R7943) normalize myogenic tone in ouabain-treated arteries. Only the NCX blockers normalize the elevated myogenic tone in α2 +/-arteries because this tone is ouabain independent. All four agents are known to lower blood pressure in salt-dependent and ouabain-induced hypertension. Thus, chronically reduced α2 activity (α2 +/-or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced α1 activity (α1 +/-) plays no persistent role: the in vivo changes in blood pressure reflect the in vitro changes in myogenic tone. Accordingly, in salt-dependent hypertension, EOLC probably increases vascular resistance and blood pressure by reducing α2 Na + pump activity and promoting Ca 2+ entry via NCX in myocytes.

Objective-Although erythrocytes have been suggested to play a role in blood clotting, mediated through phosphatidylserine (PS) exposure and/or PS-bearing microvesicle generation, an endogenous substance that triggers the membrane alterations leading to a procoagulant activity in erythrocytes has not been reported. We now demonstrated that lysophosphatidic acid (LPA), an important lipid mediator in various pathophysiological processes, induces PS exposure and procoagulant microvesicle generation in erythrocytes, which represent a biological significance resulting in induction of thrombogenic activity. Methods and Results-In human erythrocytes, LPA treatment resulted in PS exposure on remnant cells and PS-bearing microvesicle generation in a concentration-dependent manner. Consistent with the microvesicle generation, scanning electron microscopic study revealed that LPA treatment induced surface changes, alteration of normal discocytic shape into echinocytes followed by spherocytes. Surprisingly, chelation of intracellular calcium did not affect LPA-induced PS exposure and microvesicle generation. On the other hand, protein kinase C (PKC) inhibitors significantly reduced PS exposure and microvesicle generation induced by LPA, reflecting the role of calcium-independent PKC. Activation of PKC was confirmed by Western blot analysis showing translocation of calcium-independent isoform, PKC, to erythrocyte membrane. The activity of flippase, which is important in the maintenance of membrane asymmetry, was also inhibited by LPA. Furthermore, LPA-exposed erythrocytes actually potentiated the thrombin generation as determined by prothrombinase assay and accelerated the coagulation process initiated by recombinant human tissue factor in plasma. The adherence of erythrocytes to endothelial cells, another important feature of thrombogenic process, was also stimulated by LPA treatment. Conclusion-These results suggested that LPA-exposed erythrocytes could make an important contribution to thrombosis mediated through PS exposure and procoagulant microvesicle generation.

Objective-Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models. Methods and Results-Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1 y/Ϫ mice, but there was little difference in Tg SMCnox1 mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1 y/Ϫ VSMCs and increased in Tg SMCnox1 cells. Tg SMCnox1 cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1 y/Ϫ cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1 y/Ϫ cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1 y/Ϫ VSMCs. Conclusions-These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation. (Arterioscler Thromb Vasc Biol. 2009;29:480-487.)Key Words: NADPH oxidase 1 Ⅲ neointima Ⅲ migration Ⅲ vascular smooth muscle Ⅲ reactive oxygen species T he abnormal intimal growth of blood vessels as a "response to injury" is key in the development of vascular occlusive diseases such as in-stent stenosis, intimal proliferation after vein grafts, and atherosclerosis; hence, it is the major limitation for the efficacy of corrective surgery. 1 Vascular smooth muscle cells (VSMCs) are a main constituent of the neointima in these lesions. After injury, VSMCs migrate to the damaged area, proliferate and elaborate extracellular matrix (ECM), largely in response to platelet-derived growth factor (PDGF) stimulation. 2 The molecular mechanisms underlying these events are poorly understood.Reactive oxygen species (ROS) such as superoxide and hydrogen peroxide mediate signal transduction pathways that contribute to the pathophysiological responses of VSMCs including migration, proliferation, apoptosis, phenotypic modulation, and hypertrophy. 3 Major sources of ROS in VSMCs, especially in pathological conditions, are the NADPH oxidase (Nox) family of enzymes. VSMCs from conduit arteries express Nox1 and Nox4, 4 whereas those from resistance arteries express Nox2 and Nox4. 5 These oxidases serve different functions within the cells, 6 presumably owing to their distinct intracellular compartmentalization and different mechanism of regulation and activation. 7 Of interest, studies have linked Nox1 to VSMC phenotypic changes including angiotensin II-...

The future of safe cell-based therapy rests on overcoming teratoma/ tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro-and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC-or hiPSC-derived cells. Taken together, these results provide the "proof of concept" that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.

Accumulating evidence supports the importance of redox signaling in the pathogenesis and progression of hypertension. Redox signaling is implicated in many different physiological and pathological processes in the vasculature. High blood pressure is in part determined by elevated total peripheral vascular resistance, which is ascribed to dysregulation of vasomotor function and structural remodeling of blood vessels. Aberrant redox signaling, usually induced by excessive production of reactive oxygen species (ROS) and/or by decreases in antioxidant activity, can induce alteration of vascular function. ROS increase vascular tone by influencing the regulatory role of endothelium and by direct effects on the contractility of vascular smooth muscle. ROS contribute to vascular remodeling by influencing phenotype modulation of vascular smooth muscle cells, aberrant growth and death of vascular cells, cell migration, and extracellular matrix (ECM) reorganization. Thus, there are diverse roles of the vascular redox system in hypertension, suggesting that the complexity of redox signaling in distinct spatial spectrums should be considered for a better understanding of hypertension.

With the advent of the Internet of Things (IoT) era, flexible sensors are regarded as one of the most important technologies for the development of humanfriendly wearable devices. Organic field-effect transistors (OFETs) based on conjugated polymers or small molecules are promising sensor platforms because they have various advantages, including high sensitivity, mechanical flexibility, and low-cost fabrication processes. OFET-based sensors enable continuous monitoring of external stimuli or target analytes with superior detection capabilities. This review describes the working principles and sensing mechanisms of various OFET-based sensors, including chemical, biological, photo, pressure, and temperature sensors, and introduces the recent progress in this field. In addition, the technical challenges and future outlook of OFETbased sensors for next-generation flexible electronics are briefly discussed.

Conjugated polymers, in general, are unstable when exposed to air, solvent, or thermal treatment, and these challenges limit their practical applications. Therefore, it is of great importance to develop new materials or methodologies that can enable organic electronics with air stability, solvent resistance, and thermal stability. Herein, we have developed a simple but powerful approach to achieve solvent-resistant and thermally stable organic electronic devices with a remarkably improved air stability, by introducing an azide cross-linkable group into a conjugated polymer. To demonstrate this concept, we have synthesized polythiophene with azide groups attached to end of the alkyl chain (P3HT-azide). Photo-cross-linking of P3HT-azide copolymers dramatically improves the solvent resistance of the active layer without disrupting the molecular ordering and charge transport. This is the first demonstration of solvent-resistant organic transistors. Furthermore, the bulk-heterojunction organic photovoltaics (BHJ OPVs) containing P3HTazide copolymers show an average efficiency higher than 3.3% after 40 h annealing at an elevated temperature of 150 °C, which represents one of the most thermally stable OPV devices reported to date. This enhanced stability is due to an in situ compatibilizer that forms at the P3HT/PCBM interface and suppresses macrophase separation. Our approach paves a way toward organic electronics with robust and stable operations.

Endothelial dysfunction is defined as impairment of the balance between endothelium-dependent vasodilation and constriction. Despite evidence of uric acid-induced endothelial dysfunction, a relationship with insulin resistance has not been clearly established. In this study, we investigated the role of vascular insulin resistance in uric acid-induced endothelial dysfunction. Uric acid inhibited insulin-induced endothelial nitric oxide synthase (eNOS) phosphorylation and NO production more substantially than endothelin-1 expression in HUVECs, with IC50 of 51.0, 73.6, and 184.2, respectively. Suppression of eNOS phosphorylation and NO production by uric acid was PI3K/Akt-dependent, as verified by the transfection with p110. Treatment of rats with the uricase inhibitor allantoxanamide induced mild hyperuricemia and increased mean arterial pressure by 25%. While hyperuricemic rats did not show systemic insulin resistance, they showed impaired vasorelaxation induced by insulin by 56%. A compromised insulin response in terms of the Akt/eNOS pathway was observed in the aortic ring of hyperuricemic rats. Coadministration with allopurinol reduced serum uric acid levels and blood pressure and restored the effect of insulin on Akt-eNOS pathway and vasorelaxation. Taken together, uric acid induced endothelial dysfunction by contributing to vascular insulin resistance in terms of insulin-induced NO production, potentially leading to the development of hypertension.-Choi, Y.-J., Yoon, Y., Lee, K.-Y., Hien, T. T., Kang, K. W., Kim, K.-C., Lee, J., Lee, M.-Y., Lee, S. M., Kang, D.-H., Lee, B.-H. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis.