Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo.

Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

Chemotherapy-induced acute vascular injury involves intracellular generation of ROS via activation of the acid sphingomyelinase pathway.

Several categories of chemotherapy confer substantial risk for late-term vascular morbidity and mortality. In the present study, we aimed to investigate the mechanism of acute chemotherapy-induced vascular injury in normal tissues. Specifically, we looked at activation of the acid sphingomyelinase (ASMase)/ceramide pathway, which leads to generation of reactive oxygen species (ROS) and induction of oxidative stress that may result in vascular injury. In particular, we focused on two distinct drugs, doxorubicin (DOX) and cisplatin (CIS) and their effects on normal endothelial cells. In vitro, DOX resulted in increased ASMase activity, intra-cellular ROS production and induction of apoptosis. CIS treatment generated significantly reduced effects in endothelial cells. In-vivo, murine femoral arterial blood flow was measured in real-time, during and after DOX or CIS administration, using fluorescence optical imaging system. While DOX caused constriction of small vessels and disintegration of large vessels' wall, CIS induced minor vascular changes in arterial blood flow, correlating with the in vitro findings. These results demonstrate that DOX induces acute vascular injury by increased ROS production, via activation of ASMase/ceramide pathway, while CIS increases ROS production and its immediate extracellular translocation, without causing detectable acute vascular injury. Our findings may potentially lead to the development of new strategies to prevent long-term cardiovascular morbidity in cancer survivors.

Isoflavone Ameliorated Oxidative Stress and Vascular Damages in Nicotine-Administrated Mice.

Nicotine has been linked to the development of abdominal aortic aneurysms. Isoflavones, a group of polyphenolic compounds, reportedly exhibit antioxidant and anti-inflammatory properties and facilitate cardiovascular protection. However, the effects of isoflavone on nicotine-induced abdominal aortic aneurysms have not yet been elucidated. The objective of the current study was to evaluate the inhibitory effect of isoflavone on nicotine-induced weakening of the aortic wall in mouse models. Nicotine reportedly increases the occurrence of abdominal aortic aneurysms by activating endothelin-1 (ET-1), angiotensinogen and the angiotensin II type 1 (AT1) receptor, leading to an increase in neutrophil elastase, oxidative stress, and matrix metalloproteinase (MMP)-2 expression, which causes vascular wall weakness and damage. Immunohistological analyses have indicated that isoflavone significantly inhibits the activation of ET-1, angiotensinogen and the AT1 receptor in nicotine-administered mice. Additionally, isoflavone suppressed elastic fiber destruction and decreased areas positive for MMP-2, neutrophil elastase, and malondialdehyde in the vascular wall of nicotine-administered mice. Considered together, these findings suggest that isoflavone shows potential for preventing vascular wall injury induced by nicotine administration, and that food containing isoflavone may protect against abdominal aortic aneurysms.

Aortic Oxidative Stress, Inflammation and DNA Damage Following Pulmonary Exposure to Cerium Oxide Nanoparticles in a Rat Model of Vascular Injury.

Pulmonary exposure to cerium oxide nanoparticles (CeO2 NPs) can occur either at the workplace, or due to their release in the environment. Inhaled CeO2 NPs are known to cross the alveolar-capillary barrier and reach various parts of the body, including the vasculature. The anticancer drug cisplatin (CP) causes vascular damage. However, the effects CeO2 NPs on vascular homeostasis in a rat model of CP-induced vascular injury remain unclear. Here, we assessed the impact and underlying mechanism of pulmonary exposure to CeO2 NPs on aorta in rats given a single intraperitoneal injection of cisplatin (CP, 6 mg/kg) to induce vascular damage. Six days later, the rats were intratracheally instilled with either CeO2 NPs (1 mg/kg) or saline (control), and various variables were studied 24 h thereafter in the aortic tissue. The concentration of reduced glutathione and the activity of catalase were significantly increased in the CP + CeO2 NPs group compared with both the CP + saline and the CeO2 NPs groups. The activity of superoxide dismutase was significantly decreased in the CP + CeO2 NPs group compared with both the CP + saline and CeO2 NPs groups. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) by the nuclei of smooth muscles and endocardial cells assessed by immunohistochemistry was significantly augmented in CeO2 NPs versus saline, in CP + saline versus saline, and in CP + CeO2 NPs versus CeO2 NPs. Moreover, the concentrations of total nitric oxide, lipid peroxidation and 8-hydroxy-2-deoxyguanosine were significantly elevated in the CP + CeO2 NPs group compared with both the CP + saline and the CeO2 NPs groups. Similarly, compared with both the CP + saline and CeO2 NPs groups, the combination of CP and CeO2 NPs significantly elevated the concentrations of interleukin-6 and tumour necrosis factor-α. Additionally, aortic DNA damage assessed by Comet assay was significantly increased in CeO2 NPs compared with saline, and in CP + saline versus saline, and all these effects were significantly aggravated by the combination of CP and CeO2 NPs. We conclude that pulmonary exposure to CeO2 NPs aggravates vascular toxicity in animal model of vascular injury through mechanisms involving oxidative stress, Nrf2 expression, inflammation and DNA damage.

Anti-cancer drugs-induced arterial injury: risk stratification, prevention, and treatment.

Vascular side effects of standard chemotherapeutic drugs and novel anti-tumor agents complicate treatment cycles, increase non-cancer-related mortality rates, and decrease the quality of life in cancer survivors. Arterial thromboembolic events (ATEE) are associated with most anti-cancer medications. Previous articles have reported a variety of vascular events including ST-segment elevation myocardial infarction as one of the most severe acute arterial attacks. Cardiologists should play an early role in identifying those at high risk for vascular complications and tailor anti-thrombotic therapies in keeping with thromboembolic and bleeding risks. Early preventive steps and individualized chemotherapy may decrease anti-tumor treatment-related vascular events. Here, we aim to provide an extensive review of anti-tumor drug-induced vascular injury (DIVI), pathomechanisms, and risk stratification underlining arterial events. We give a summary of clinical manifestations, treatment options, and possible preventive measures of DIVI. Additionally, the treatment of modifiable risk factors and tailored choice of chemotherapy must be considered in all oncology patients to prevent DIVI. We propose a complex tool for ATEE risk stratification which is warranted for early prediction leading to less frequent complications in cancer patients.

Inducible Knockdown of Endothelial Protein Tyrosine Phosphatase-1B Promotes Neointima Formation in Obese Mice by Enhancing Endothelial Senescence.

AIMS: Protein tyrosine phosphatase-1B (PTP1B) is a negative regulator of receptor tyrosine kinase signaling. In this study, we determined the importance of PTP1B expressed in endothelial cells for the vascular response to arterial injury in obesity. RESULTS: Morphometric analysis of vascular lesions generated by 10% ferric chloride (FeCl3) revealed that tamoxifen-inducible endothelial PTP1B deletion (Tie2.ERT2-Cre × PTP1Bfl/fl; End.PTP1B knockout, KO) significantly increased neointima formation, and reduced numbers of (endothelial lectin-positive) luminal cells in End.PTP1B-KO mice suggested impaired lesion re-endothelialization. Significantly higher numbers of proliferating cell nuclear antigen (PCNA)-positive proliferating cells as well as smooth muscle actin (SMA)-positive or vascular cell adhesion molecule-1 (VCAM1)-positive activated smooth muscle cells or vimentin-positive myofibroblasts were detected in neointimal lesions of End.PTP1B-KO mice, whereas F4/80-positive macrophage numbers did not differ. Activated receptor tyrosine kinase and transforming growth factor-beta (TGFß) signaling and oxidative stress markers were also significantly more abundant in End.PTP1B-KO mouse lesions. Genetic knockdown or pharmacological inhibition of PTP1B in endothelial cells resulted in increased expression of caveolin-1 and oxidative stress, and distinct morphological changes, elevated numbers of senescence-associated ß-galactosidase-positive cells, and increased expression of tumor suppressor protein 53 (p53) or the cell cycle inhibitor cyclin-dependent kinase inhibitor-2A (p16INK4A) suggested senescence, all of which could be attenuated by small interfering RNA (siRNA)-mediated downregulation of caveolin-1. In vitro, senescence could be prevented and impaired re-endothelialization restored by preincubation with the antioxidant Trolox. INNOVATION: Our results reveal a previously unknown role of PTP1B in endothelial cells and provide mechanistic insights how PTP1B deletion or inhibition may promote endothelial senescence. CONCLUSION: Absence of PTP1B in endothelial cells impairs re-endothelialization, and the failure to induce smooth muscle cell quiescence or to protect from circulating growth factors may result in neointimal hyperplasia.

Murine models of vascular endothelial injury: Techniques and pathophysiology.

Vascular endothelial injury (VEI) triggers pathological processes in various cardiovascular diseases, such as coronary heart disease and hypertension. To further elucidate the in vivo pathological mechanisms of VEI, many animal models have been established. For the easiness of genetic manipulation and feeding, murine models become most commonly applied for investigating VEI. Subsequently, countless valuable information concerning pathogenesis has been obtained and therapeutic strategies for VEI have been developed. This review will highlight some typical murine VEI models from the perspectives of pharmacological intervention, surgery and genetic manipulation. The techniques, pathophysiology, advantages, disadvantages and the experimental purpose of each model will also be discussed.

Transplantation of skin mesenchymal stem cells attenuated AngII-induced hypertension and vascular injury.

Skin mesenchymal stem cells (S-MSCs) revealed an important immunomodulatory activity to markedly suppress the formation of the atherosclerosis (AS) plaque by modulating macrophages, and also inhibit the development of experimental autoimmune encephalomyelitis (EAE) by regulating T helper 17 (Th17) cell differentiation. Macrophages and Th17 cells play important roles in hypertension. However, it remains unclear whether S-MSCs are capable of improving angiotensin (AngII)-induced hypertension by acting on inflammatory cells. Therefore, we studied a direct effect of S-MSC treatment on an AngII-induced hypertensive mouse model. Twenty-seven C57BL/6 (WT) mice were divided into three groups: Control group (WT-NC), AngII-infused group (WT-AngII), and S-MSC treatment group (WT-AngII + S-MSCs). In contrast to WT-AngII group, systolic blood pressure (SBP) and vascular damage were strikingly attenuated after tail-vein injection of S-MSCs. Numbers of Th17 cells in mouse peripheral blood of S-MSC treated group were significantly decreased, and IL-17 mRNA and protein levels were also reduced in the aorta and serum compared with WT-AngII group. Furthermore, macrophages in S-MSC treated group were switched to a regulatory profile characterized by a low ability to produce pro-inflammatory cytokine TNF-α and a high ability to produce anti-inflammatory cytokines Arg1 and IL-10. Mechanistically, we found that S-MSCs inhibited Th17 cell differentiation and induced M2 polarization. Moreover, we found proliferation and migration of S-MSCs were elevated, and expression of CXCR4, the receptor for Stromal derivated factor -1(SDF-1), was markedly increased in lipopolysaccharide (LPS)- stimulated S-MSCs. Given that SDF-1 expression was increased in the serum and aorta in AngII- induced hypertensive mice, the immunomodulatory effects exerted by S-MSCs involved the CXCR4/SDF-1 signaling. Collectively, our data demonstrated that S-MSCs attenuated AngII-induced hypertension by inhibiting Th17 cell differentiation and by modulating macrophage M2 polarization, suggesting that S-MSCs potentially have a role in stem cell based therapy for hypertension.

An Overview of Vascular Adverse Events Associated With Facial Soft Tissue Fillers: Recognition, Prevention, and Treatment.

Minimally invasive facial cosmetic surgery procedures have seen an exponential increase in numbers over the past decade. The most commonly performed procedures are neuromodulator and soft tissue filler procedures. Although soft tissue fillers have a high safety and predictability profile, these procedures recently have been associated with serious and dire adverse events. This article will discuss some of the vascular complications associated with facial soft tissue fillers. Management and prevention of these adverse events also will be discussed.

The Far Side of Vascular Injury: Nonconventional Vasoconstrictors, DNA-targeting Agents, and Agents Toxic to Vascular Smooth Muscle.

Substances historically thought to cause direct vascular injury in laboratory animals are a heterogeneous group of toxic agents with varied mechanisms of action. Morphologically, the reviewed agents can be broadly categorized into those targeting endothelial cell (ECs) and those targeting smooth muscle cells (SMCs). Anticancer drugs, immunosuppressants, and heavy metals are targeting primarily ECs while allylamine, ß-aminopropionitrile, and mitogen-activated protein kinase kinase inhibitors affect mainly SMCs. It is now recognized that the pathogenicity of some of these agents is often mediated through intermediary events, particularly vasoconstriction. There are clear similarities in the clinical and microscopic findings associated with many of these agents in animals and man, allowing the use of animal models to investigate mechanisms and pathogenesis. The molecular pathogenic mechanisms and comparative morphology in animals and humans will be reviewed.

Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat.

Recombinant interleukin-2 (rIL-2) administration in oncology indications is hampered by vascular toxicity, which presents as a vascular leak syndrome. We used this aspect of the toxicity of rIL-2 to evaluate candidate biomarkers of drug-induced vascular injury (DIVI) in rats given 0.36 mg/kg rIL-2 daily. Groups of rats were given either 2 or 5 doses of rIL-2 or 5 doses of rIL-2 followed by a 7-day recovery. The histomorphologic lexicon and grading scheme developed by the Vascular Injury Working Group of the Predictive Safety Testing Consortium of the Critical Path Institute were utilized to enable semiquantitative integration with circulating biomarker levels. The administration of rIL-2 was associated with time-dependent endothelial cell hyperplasia and hypertrophy and perivascular inflammation that correlated with increases in circulating angiopoietin-2, lipocalin-2, monocyte chemotactic protein-1, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor A, E-selectin, and chemokine (C-X-C motif) ligand-1, and the microRNAs miR-21, miR-132, and miR-155. The dose groups were differentially identified by panels comprising novel candidate biomarkers and traditional hematologic parameters. These results identify biomarkers of the early stages of DIVI prior to the onset of vascular smooth muscle necrosis.

Roflumilast-induced Local Vascular Injury Is Associated with a Coordinated Proteome and Microparticle Change in the Systemic Circulation in Pigs.

Drug-induced vascular injury (DIVI) is commonly associated with phosphodiesterase (PDE) inhibitors. Despite histological characterization, qualified biomarkers for DIVI detection are lacking. We investigated whether a single administration of roflumilast (PDE-IV inhibitor) induces vascular damage and identified novel surrogate biomarkers of acute vascular injury. Pigs received postoperative 250, 375, or 500 µg of roflumilast or placebo/control. After 1.5 hr, coronary reactivity was determined by catheter-based administration of acetylcholine and sodium nitroprusside (SNP) in the coronary sinus. Immunohistochemical analysis of vessel integrity (von Willebrand factor [vWF]) and fibrin(ogen) deposition was performed in the coronary artery and aorta. Peripheral blood was collected for differential proteomics and microparticles analysis. Circulating interleukin (IL)-6 was analyzed. Roflumilast-treated animals displayed higher vasodilation to acetylcholine and SNP versus controls (p < .05). Roflumilast-treated animals showed a dose-dependent (p < .05) decrease in vessel integrity and dose-dependent increase in fibrin deposition forming a continuous layer at roflumilast-500 µg. Peripheral blood of roflumilast-500-µg-treated animals showed increased levels of total and endothelial-derived microparticles and exhibited a coordinated change in proteins kininogen-1, endothelin-1, gelsolin, apolipoprotein A-I, and apolipoprotein-J associated with vascular injury (p < .05 vs. controls). IL-6 remained unaltered. Roflumilast-induced vascular injury can be detected by novel markers in peripheral blood. Validation of these surrogate markers in human samples seems required.

Aspirin enhances protective effect of fish oil against thrombosis and injury-induced vascular remodelling.

BACKGROUND AND PURPOSE: Although aspirin (acetylsalicylic acid) is commonly used to prevent ischaemic events in patients with coronary artery disease, many patients fail to respond to aspirin treatment. Dietary fish oil (FO), containing ω3 polyunsaturated fatty acids (PUFAs), has anti-inflammatory and cardio-protective properties, such as lowering cholesterol and modulating platelet activity. The objective of the present study was to investigate the potential additional effects of aspirin and FO on platelet activity and vascular response to injury. EXPERIMENTAL APPROACH: Femoral arterial remodelling was induced by wire injury in mice. Platelet aggregation, and photochemical- and ferric chloride-induced carotid artery thrombosis were employed to evaluate platelet function. KEY RESULTS: FO treatment increased membrane ω3 PUFA incorporation, lowered plasma triglyceride and cholesterol levels, and reduced systolic BP in mice. FO or aspirin alone inhibited platelet aggregation; however, when combined, they exhibited synergistic suppression of platelet activity in mice, independent of COX-1 inhibition. FO alone, but not aspirin, attenuated arterial neointimal growth in response to injury. Strikingly, a combination of FO and aspirin synergistically inhibited injury-induced neointimal hyperplasia and reduced perivascular inflammatory reactions. Moreover, co-administration of FO and aspirin decreased the expression of pro-inflammatory cytokines and adhesion molecules in inflammatory cells. Consistently, a pro-resolution lipid mediator-Resolvin E1, was significantly elevated in plasma in FO/aspirin-treated mice. CONCLUSIONS AND IMPLICATIONS: Co-administration of FO and low-dose aspirin may act synergistically to protect against thrombosis and injury-induced vascular remodelling in mice. Our results support further investigation of adjuvant FO supplementation for patients with stable coronary artery disease.

MMP-12 deficiency attenuates angiotensin II-induced vascular injury, M2 macrophage accumulation, and skin and heart fibrosis.

MMP-12, a macrophage-secreted elastase, is elevated in fibrotic diseases, including systemic sclerosis (SSc) and correlates with vasculopathy and fibrosis. The goal of this study was to investigate the role of MMP-12 in cardiac and cutaneous fibrosis induced by angiotensin II infusion. Ang II-induced heart and skin fibrosis was accompanied by a marked increase of vascular injury markers, including vWF, Thrombospondin-1 (TSP-1) and MMP-12, as well as increased number of PDGFRß+ cells. Furthermore Ang II infusion led to an accumulation of macrophages (Mac3+) in the skin and in the perivascular and interstitial fibrotic regions of the heart. However, alternatively activated (Arg 1+) macrophages were mainly present in the Ang II infused mice and were localized to the perivascular heart regions and to the skin, but were not detected in the interstitial heart regions. Elevated expression of MMP-12 was primarily found in macrophages and endothelial cells (CD31+) cells, but MMP-12 was not expressed in the collagen producing cells. MMP-12 deficient mice (MMP12KO) showed markedly reduced expression of vWF, TSP1, and PDGFRß around vessels and attenuation of dermal fibrosis, as well as the perivascular fibrosis in the heart. However, MMP-12 deficiency did not affect interstitial heart fibrosis, suggesting a heterogeneous nature of the fibrotic response in the heart. Furthermore, MMP-12 deficiency almost completely prevented accumulation of Arg 1+ cells, whereas the number of Mac3+ cells was partially reduced. Moreover production of profibrotic mediators such as PDGFBB, TGFß1 and pSMAD2 in the skin and perivascular regions of the heart was also inhibited. Together, the results of this study show a close correlation between vascular injury markers, Arg 1+ macrophage accumulation and fibrosis and suggest an important role of MMP-12 in regulating these processes.

The role of eNOS phosphorylation in causing drug-induced vascular injury.

Previously we found that regulation of eNOS is an important part of the pathogenic process of Drug-induced vascular injury (DIVI) for PDE4i. The aims of the current study were to examine the phosphorylation of eNOS in mesentery versus aorta at known regulatory sites across DIVI-inducing drug classes and to compare changes across species. We found that phosphorylation at S615 in rats was elevated 35-fold 2 hr after the last dose of CI-1044 in mesentery versus 3-fold in aorta. Immunoprecipitation studies revealed that many of the upstream regulators of eNOS activation were associated with eNOS in 1 or more signalosome complexes. Next rats were treated with drugs from 4 other classes known to cause DIVI. Each drug was given alone and in combination with SIN-1 (NO donor) or L-NAME (eNOS inhibitor), and the level of eNOS phosphorylation in mesentery and aorta tissue was correlated with the extent of vascular injury and measured serum nitrite. Drugs or combinations produced altered serum nitrite levels as well as vascular injury score in the mesentery. The results suggested that phosphorylation of S615 may be associated with DIVI activity. Studies with the species-specific A2A adenosine agonist CI-947 in rats versus primates showed a similar pattern.

Vascular origin of vildagliptin-induced skin effects in Cynomolgus monkeys: pathomechanistic role of peripheral sympathetic system and neuropeptide Y.

The purpose of this article is to characterize skin lesions in cynomolgus monkeys following vildagliptin (dipeptidyl peptidase-4 inhibitor) treatment. Oral vildagliptin administration caused dose-dependent and reversible blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and sores involving the extremities at ≥5 mg/kg/day and necrosis of the tail and the pinnae at ≥80 mg/kg/day after 3 weeks of treatment. At the affected sites, the media and the endothelium of dermal arterioles showed hypertrophy/hyperplasia. Skin lesion formation was prevented by elevating ambient temperature. Vildagliptin treatment also produced an increase in blood pressure and heart rate likely via increased sympathetic tone. Following treatment with vildagliptin at 80 mg/kg/day, the recovery time after lowering the temperature in the feet of monkeys and inducing cold stress was prolonged. Ex vivo investigations showed that small digital arteries from skin biopsies of vildagliptin-treated monkeys exhibited an increase in neuropeptide Y-induced vasoconstriction. This finding correlated with a specific increase in NPY and in NPY1 receptors observed in the skin of vildagliptin-treated monkeys. Present data provide evidence that skin effects in monkeys are of vascular origin and that the effects on the NPY system in combination with increased peripheral sympathetic tone play an important pathomechanistic role in the pathogenesis of cutaneous toxicity.

Biomarkers of endothelial cell activation: candidate markers for drug-induced vasculitis in patients or drug-induced vascular injury in animals.

There is a pressing need for vascular biomarkers for studies of drug-induced vasculitis in patients and drug-induced vascular injury (DIVI) in animals. We previously reviewed a variety of candidate biomarkers of endothelial cell (EC) activation (Zhang et al., 2010). Now we update information on EC activation biomarkers from animal data on DIVI and clinical data of vasculitic patients, particularly patients with primary antineutrophil cytoplasmic autoantibody (ANCA)-associated small vessel vasculitis (primary AAVs), including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and necrotizing crescentic glomerulonephritis. Drug-associated ANCA-positive small vessel vasculitis (drug-AAVs) can closely resemble primary AAVs, suggesting the large overlap between primary idiopathic systemic vasculitis and drug-induced vasculitis. AAVs in patients and DIVI in animals vary considerably; however, there is close resemblance between AAVs and DIVI in some respects: (1) the immunopathogenetic mechanisms (activation of primed neutrophils, ECs and T cells by ANCA in patients and activation of ECs, mast cells, and macrophages by drugs in animals); (2) the morphologic changes (fibrinoid necrosis of the vessel wall and neutrophilic infiltration); (3) the preferable sites (small arteries, arterioles, capillaries and venules); and (4) elevation of vascular biomarkers suggestive of an endothelial origin. The present review discusses soluble and cell component biomarkers and provides a rationale for the potential utility of EC activation biomarkers in nonclinical and clinical studies during new drug development. Further investigation, however, is needed to assess their potential utility.

Intravenous low redox potential saline attenuates FeCl3-induced vascular dysfunction via downregulation of endothelial H2O2, CX3CL1, intercellular adhesion molecule-1, and p53 expression.

Exaggerated reactive oxygen species (ROS) may contribute to vascular injury by the enhancement of CX3CL1, intercellular adhesion molecule-1 (ICAM-1), and pro-apoptotic p53 expression. Reduced water with safely antioxidant activity may protect vascular tissue against oxidative injury. We established reduced water (RW) by using a modified magnesium alloy and evaluated the effects of an RW-made culture medium on TNF-α-induced endothelial damage in vitro and intravenous RW-made saline (0.9%NaCl) infusion on FeCl(3)-induced arterial injury in rats in vivo. Several oxidative stresses were evaluated by using a chemiluminescence analyzer, Western blot, and immunohistochemistry. We found that the established RW, RW-culture medium, and RW saline displayed a lower redox potential (<-150 mV) and efficient H(2)O(2) scavenging activity compared with distilled-water-made solutions. The RW-culture medium significantly depressed TNF-α-enhanced endothelial H(2)O(2) production; improved CX3CL1, ICAM-1, and p53 expression; and inhibited activated monocyte adhesion to endothelial cells as well as to the CX3CL1 or the ICAM-1 coated plate when compared with the distilled-water-culture medium. In the in vivo study, the time required for FeCl(3)-induced occlusion in the urethane anesthetized rat's carotid and femoral arteries was significantly extended by intravenous RW saline infusion compared with distilled-water saline. FeCl(3) stimulation significantly enhanced vascular NADPH oxidase activity, ROS production, as well as CX3CL1, ICAM-1, p53, 3-nitrotyrosine, and 4-hydroxynonenal expression in the damaged arteries. Intravenous RW saline significantly reduced all the FeCl(3)-enhanced oxidative parameters when compared with intravenous distilled-water-saline infusion. We conclude that the RW-culture medium and saline made from magnesium alloy confer cardiovascular protection by the antioxidant capability.

Vascular injury following accidental intra-arterial injection of clindamycin: adverse drug reaction report.

Clindamycin in a commonly used antibiotic, considered safe for oral, intravenous and intra-arterial use. We present a case of a patient that received an inadvertent injection clindamycin 600 mg in 4 mL through a radial arterial line. The patient presented signs and symptoms of vascular occlusion and despite aggressive pharmacological and medical treatment developed massive and severe tissue injury.