Rationale Chronic exposure to ambient air-borne particulate matter <2.5 µm (PM2.5) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. Objective To investigate the molecular mechanisms by which PM2.5 mediates inflammatory responses in a mouse model of chronic exposure. Methods and Results Here we show that chronic exposure to ambient PM2.5 promotes Ly6Chigh inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor-4 (TLR4) and Nox2 (gp91phox) deficiency prevented monocyte NADPH oxidase activation in response to PM2.5 and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47phox phosphorylation in TLR4 deficient animals. PM2.5 exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone-marrow derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM2.5 exposure while TLR4 deficiency attenuated this response. Conclusions Taken together, our findings suggest that PM2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase dependent mechanisms.

Aims Alpha-lipoic acid (LA) is a commonly used dietary supplement that exerts anti-oxidant and anti-inflammatory effects in vivo and in vitro. We investigated the mechanisms by which LA may confer protection in models of established atherosclerosis. Main Methods Watanabe heritable hyperlipidemic (WHHL) rabbits were fed with high cholesterol chow for 6 weeks and then randomized to receive either high cholesterol diet alone or combined with LA (20 mg/kg/day) for 12 weeks. Vascular function was analyzed by myography. The effects of LA on T cell migration to chemokine gradients was assessed by Boyden chamber. NF-κB activation was determined by measuring translocation and electrophoresis migration shift assay (EMSA). Key findings LA decreased body weight by 15 ± 5% without alterations in lipid parameters. Magnetic Resonance Imaging (MRI) analysis demonstrated that LA reduced atherosclerotic plaques in the abdominal aorta, with morphological analysis revealing reduced lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, LA improved vascular reactivity (decreased constriction to angiotensin II and increased relaxation to acetylcholine and insulin), inhibited NF-κB activation, and decreased oxidative stress and expression of key adhesion molecules in the vasculature. LA reduced T cell content in atherosclerotic plaque in conjunction with decreasing ICAM and CD62L (L-Selectin) expression. These effects were confirmed by demonstration of a direct effect of LA in reducing T cell migration in response to CCL5 and SDF-1 and decreasing T cell adhesion to the endothelium by intra-vital microscopy Significance The present findings offer a mechanistic insight into the therapeutic effects of LA on atherosclerosis.

Background: Post-myocardial infarction (MI) ventricular septal defects (PIVSD) are an uncommon but life-threatening complication of acute MI. Although surgical closure has been the standard of care, mortality, and recurrence of VSD remain high even after emergent surgery. Transcatheter VSD closure (TCC) devices have become an alternative or adjunct to surgical closure.Methods: Online database search was performed for studies that included adults with PIVSD who underwent medical treatment (MT) alone, surgical closure (SC) (early or late), and TCC (early, late, or for post-surgical residual VSD).Results: Twenty-six studies were included with a total of 737 patients who underwent either MT (N = 100), SC (early (n = 167), late (n = 100)), and TCC (early (n = 176), late (n = 115), or post-surgical residual VSD (n = 79)). The 30-day mortality among MT group was 92 ± 6.3%, among SC was 61 ± 22.5% (early 56 ± 23%, late 41 ± 30%), and for all TCC patients was 33 ± 24% (early 54 ± 32.7%, late 16 ± 26%), and TCC for post-surgical residual VSD 11 ± 34.9%. The mortality among overall SC, overall TCC and early TCC groups was significantly lower as compared with the MT (P < 0.001 for all comparisons).The overall mortality among all TCC, and late TCC groups was significantly lower when compared with the late SC (P < 0.0001, P < 0.0001, respectively). Conclusion: Closure of PIVSD decreases mortality as compared with MT alone and should be attempted as early as possible after diagnosis. Selection of TCC versus SC should be based on factors including complexity of the defect, availability of closure devices, expertise of the operator, and clinical condition of patient. K E Y W O R D S closure device, management, post-infarction VSD, transcatheter

Objective Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis. Methods and Results Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factor–κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2). Conclusion INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor–κB signaling.

Increasing life expectancy has made old age-related health problems like dementia and cognitive decline more prevalent, and these are rapidly becoming important causes of disability and poor quality of life, causing significant add-ons to health-care costs worldwide. Hypertension is the most important modifiable vascular risk factor for the development and progression of both cognitive decline and dementia. In many observational and randomized studies, antihypertensive therapies have been shown to be beneficial in slowing cognitive decline. However, due to observed discrepancies by these studies, there is a lack of consensus on the best antihypertensive strategy for the prevention or slowing of cognitive decline. It is also not clear whether the beneficial effect of antihypertensive therapy is due to the use of a specific class of agents or combination therapy. Thus, we present a comprehensive review of overall antihypertensive therapies and cognition and of the individual antihypertensive therapy classes with their specific protective mechanisms and available clinical evidence behind their effect on cognitive function.