There is a critical need for cerebro-protective interventions to improve the suboptimal outcomes of patients with ischemic stroke who have been treated reperfusion strategies. We found that nuclear pyruvate kinase muscle 2 (PKM2), modulator systemic inflammation, was upregulated in neutrophils after onset both humans and mice. Therefore, we determined role PKM2 pathogenesis by using murine models preexisting comorbidities. generated novel myeloid cell-specific PKM2-/- mice on wild-type...

The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role cell type-specific setting atherosclerosis remains to be defined. We determined whether myeloid cell-specific regulates efferocytosis and atherosclerosis.

Fibronectin–splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication neointimal hyperplasia remains unclear. Herein, using human coronary artery sections a bare metal stent, we demonstrate the expression vicinity SMC-rich neointima and peri-strut areas. In mice, colocalizes SMCs injured carotid arteries promotes formation comorbid condition...

Triacylglycerol (TG) accumulation caused by adipose triglyceride lipase (ATGL) deficiency or very low-density lipoprotein (VLDL) loading of wild-type (Wt) macrophages results in mitochondrial-mediated apoptosis. This phenotype is correlated to depletion Ca2+ from the endoplasmic reticulum (ER), an event known induce unfolded protein response (UPR). Here, we show that ER stress TG-rich activates UPR, resulting increased abundance chaperone GRP78/BiP, induction pancreatic kinase-like kinase,...

Objective— Cellular fibronectin containing extra domain A (EDA + -FN) is abundant in the arteries of patients with atherosclerosis. Several vitro studies suggest that EDA -FN interacts Toll-like receptor 4 (TLR4). We tested hypothesis exacerbates atherosclerosis through TLR4 a clinically relevant model atherosclerosis, apolipoprotein E–deficient ( Apoe −/− ) mouse. Approach and Results— The extent was evaluated whole aortae cross sections aortic sinus male female mice (which lack -FN), fl/fl...

von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF (Plt-VWF) biochemically different from the cell-derived (EC-VWF). However, little about relative contribution of pools stroke.Using bone marrow transplantation, we generated chimeric Plt-VWF mice, mice lack ADAMTS13 platelets plasma (Plt-VWF/Adamts13(-/-)), EC-VWF determine stroke. brain ischemia/reperfusion injury...

Currently, there is no effective intervention available that can reduce brain damage following reperfusion. Clinical studies suggest a positive correlation between the increased influx of neutrophils and severity injury Integrin α9β1 highly expressed on activated contributes to stable adhesion, but its role in stroke outcome has not been demonstrated date.

Objective: The role of glycolytic enzyme PKM2 (pyruvate kinase muscle 2) in smooth cell (SMC) phenotype switching and neointimal hyperplasia is poorly understood. We determined the SMC hyperplasia. Approach Results: show that expressed SMC-rich neointima murine carotid artery peri-strut areas bare-metal stented human coronary arteries. PDGF-BB (platelet-derived growth factor-BB) stimulation upregulates expression cultured SMC. To provide conclusive evidence for function, we generated...

Scope Xanthohumol (XN), a prenylated antioxidative and anti‐inflammatory chalcone from hops, exhibits positive effects on lipid glucose metabolism. Based its favorable biological properties, we investigated whether XN attenuates atherosclerosis in western‐type diet‐fed apolipoprotein‐E‐deficient ( ApoE −/− ) mice. Methods results supplementation markedly reduced plasma cholesterol concentrations, decreased atherosclerotic lesion area, attenuated concentrations of the proinflammatory cytokine...

VWF (von Willebrand factor) is synthesized by endothelial cells and megakaryocytes known to contribute atherosclerosis. In vitro studies suggest that platelet-derived (Plt-VWF) biochemically functionally different from cell-derived (EC-VWF). We determined the role of pools in pathophysiology atherosclerosis.Using bone marrow transplantation, we generated chimeric Plt-VWF, EC-VWF, Plt-VWF mice lacking a disintegrin metalloprotease with thrombospondin type I repeats-13 platelets plasma on...

The fibronectin-splicing variant containing extra domain A (Fn-EDA) is present in negligible amounts the plasma of healthy humans but markedly elevated patients with comorbid conditions, including diabetes mellitus and hypercholesterolemia, which are risk factors for stroke. It remains unknown, however, whether Fn-EDA worsens stroke outcomes such conditions. We determined role outcome a model apolipoprotein E-deficient (Apoe(-/-)) mouse.In transient cerebral ischemia/reperfusion injury...

Background and aimsMonoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol fatty acid. MGL also hydrolyzes thereby deactivates 2-arachidonoyl (2-AG), most abundant endocannabinoid in mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) CB2R, which are mainly expressed brain immune cells, respectively. Thus, we speculated that absence MGL, increased concentrations mediate CB2R signaling cells modulate...

Reperfusion injury can exacerbate tissue damage in ischemic stroke, but little is known about the mechanisms linking ROS to stroke severity. Here, we tested hypothesis that protein methionine oxidation potentiates NF-κB activation and contributes cerebral ischemia/reperfusion injury. We found overexpression of sulfoxide reductase A (MsrA), an antioxidant enzyme reverses oxidation, attenuated ROS-augmented endothelial cells, part, by protecting against residues regulatory domain...

Background and Purpose- Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells elevated circulation patients with cardiovascular diseases. Although global deficiency of mice improves stroke outcome, the specific contribution plasma versus endothelium outcome currently unknown. We investigated role exacerbation comorbid condition hyperlipidemia. Methods- generated novel Fn-EDA-/- ( fl/fl Alb Cre) Tie2 strains on hyperlipidemic apolipoprotein...

Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9β1 expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) tenascin C. Although myeloid deletion of α9 reduces susceptibility ischemic stroke, it unclear whether this mediated by neutrophil-derived α9. We determined role neutrophil-specific in stroke outcomes mice model with obesity-induced hyperglycemia.

Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play crucial role in SMC biology by binding to the extracellular matrix protein with actin cytoskeleton within SMC. Integrin α9 plays an important cell motility and autoimmune diseases; however, its remodeling unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate expression. Targeting SMCs, using...

Triacylglycerols (TG) are the major storage molecules of metabolic energy and fatty acids in several tissues. The final step TG biosynthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Lack whole body DGAT1 associated with reduced lipid-induced inflammation. Since one component atherosclerosis chronic inflammation we hypothesized that deficiency might ameliorate atherosclerotic lesion development. We therefore crossbred Apolipoprotein E-deficient (ApoE(-/-)) mice...

During autophagy, autophagosomes fuse with lysosomes to degrade damaged organelles and misfolded proteins. Breakdown products are released into the cytosol contribute energy metabolic building block supply, especially during starvation. Lipophagy has been defined as autophagy-mediated degradation of lipid droplets (LDs) by lysosomal acid lipase. Adipose triglyceride lipase (ATGL) is major enzyme catalyzing initial step lipolysis hydrolyzing triglycerides (TGs) in cytosolic LDs. Consequently,...

Background Fibronectin splicing variant containing extra domain A (Fn-EDA), which is an endogenous ligand for Toll-like receptor 4 (TLR4), present in negligible amounts the plasma of healthy humans, but markedly elevated patients with co-morbid conditions including diabetes and hyperlipidaemia, are risk factors myocardial infarction (MI). Very little known about role Fn-EDA pathophysiology acute MI under these conditions. Materials Methods We determined ischaemia/reperfusion (I/R) injury...

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) prevents microvascular thrombosis by cleaving prothrombogenic ultralarge von Willebrand factor (VWF) multimers. Clinical studies have found association between reduced ADAMTS13-specific activity, VWF multimers, thrombotic angiopathy in patients diabetic nephropathy. It remains unknown, however, whether deficiency or multimers a causative effect nephropathy.The extent of renal injury was evaluated wild-type...

Fibronectin containing extra domain A (Fn-EDA) is an endogenous ligand of TLR4 (toll-like receptor 4) and abundant in the extracellular matrix advanced atherosclerotic lesions human mice. Irrespective sex, deletion Fn-EDA reduces early atherosclerosis apolipoprotein E-deficient (Apoe-/-) However, contribution remains poorly characterized. We determined aged (1-year-old) Apoe-/- mice.Plaque composition was innominate artery, a plaque instability site that known to mimic several histological...

The extracellular matrix of atherosclerotic arteries contains abundant deposits cellular Fn-EDA (fibronectin containing extra domain A), suggesting a functional role in the pathophysiology atherosclerosis. is synthesized by several cell types, including endothelial cells (ECs) and smooth muscle (SMCs), which are known to contribute different stages Although previous studies using global Fn-EDA-deficient mice have demonstrated that proatherogenic, cell-specific EC versus SMC-derived-Fn-EDA...