PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells.

Background: Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness.

In vitro biological responses of plasma nanocoatings for coronary stent applications.

In-stent restenosis and thrombosis remain to be long-term challenges in coronary stenting procedures. The objective of this study was to evaluate the in vitro biological responses of trimethylsilane (TMS) plasma nanocoatings modified with NH /O (2:1 molar ratio) plasma post-treatment (TMS + NH /O nanocoatings) on cobalt chromium (CoCr) alloy L605 coupons, L605 stents, and 316L stainless steel (SS) stents. Surface properties of the plasma nanocoatings with up to 2-year aging time were characterized by wettability assessment and x-ray photoelectron spectroscopy (XPS).

A Biocompatibility Study of Plasma Nanocoatings onto Cobalt Chromium L605 Alloy for Cardiovascular Stent Applications.

The objective of this study was to evaluate the biocompatibility of trimethylsilane (TMS) plasma nanocoatings modified with NH/O (2:1 molar ratio) plasma post-treatment onto cobalt chromium (CoCr) L605 alloy coupons and stents for cardiovascular stent applications. Biocompatibility of plasma nanocoatings was evaluated by coating adhesion, corrosion behavior, ion releasing, cytotoxicity, and cell proliferation. Surface chemistry and wettability were studied to understand effects of surface properties on biocompatibility.

CagA , Not CagA , Infection Impairs Endothelial Function Through Exosomes-Mediated ROS Formation.

Background: infection increases the risk for atherosclerosis, and ROS are critical to endothelial dysfunction and atherosclerosis. CagA is a major virulence factor associated with atherosclerosis. The present study aimed to test the hypothesis that CagA effectively colonizes gastric mucosa, and CagA , but not CagA , infection impairs endothelial function through exosomes-mediated ROS formation.

Fish Oil Supplements for Prevention of Cardiovascular Disease: The Jury Is Still Out: CON: Fish Oil is Useful to Prevent or Treat Cardiovascular Disease.

Consumption of oily fish high in omega-3 fatty acids (n-3FAs) is strongly associated with reduced risk of adverse cardiovascular events. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the n-3FAs in fish oil believed to confer its beneficial effects. Over the past two decades, multiple clinical trials have been conducted to test the hypothesis that encapsulated EPA and DHA supplements improve cardiovascular outcomes in patients with established cardiovascular disease or at risk of developing it.

Janus Kinase 3 Deficiency Promotes Vascular Reendothelialization-Brief Report.

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Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1.

Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors.

Drug Targeting of Plasminogen Activator Inhibitor-1 Inhibits Metabolic Dysfunction and Atherosclerosis in a Murine Model of Metabolic Syndrome.

Objective: Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome.

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise.

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity.

Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.

Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses.

Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation.

Objective: Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo.

Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis.

In our efforts to develop new approaches to treat and prevent human vascular diseases, we report herein our results on the proliferation and migration of human smooth muscles cells (SMCs) and endothelial cells (ECs) using epigallocatechin-3-gallate conjugated gold nanoparticles (EGCg-AuNPs) as possible alternatives to drug coated stents. Detailed in vitro stability studies of EGCg-AuNPs in various biological fluids, affinity and selectivity towards SMCs and ECs have been investigated. The EGCg-AuNPs showed selective inhibitory efficacy toward the migration of SMCs.

The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4.

Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI.

Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma.

Background: An increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model.

Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk.

Objective: Plasminogen activator inhibitor-1 (PAI-1) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion. However, no previous study has implicated PAI-1 in controlling vascular endothelial growth factor (VEGF) signaling. We tested the hypothesis that PAI-1 downregulates VEGF receptor-2 (VEGFR-2) activation by inhibiting a vitronectin-dependent cooperative binding interaction between VEGFR-2 and αVβ3.

Almost everyone over 50 should be put on a statin to reduce the risk of cardiovascular disease: A contrarian view.

3-Hydroxy-3-methyl-glutarylCoA reductase inhibitors, or statins, are a mainstay in the treatment of patients with established coronary artery disease (CAD) because of their proven efficacy in reducing cardiovascular death, myocardial infarction, and coronary revascularization procedures in this patient population. Statin therapy has also proven successful in the primary prevention of CAD. However, the absolute reduction in cardiovascular events is lower in primary prevention than in secondary prevention trials, and many of the primary prevention trials enrolled a significant number of patients with established cardiovascular disease and/or other high-risk features, such as diabetes mellitus.

Homocysteine and thrombosis: guilt by association?

The long-recognized connection between homocysteine and thrombosis is examined in this issue of Blood in a study conducted by Dayal and colleagues. The results challenge the proposed mechanisms by which disordered homocysteine metabolism triggers vascular disease.

Antecedent hydrogen sulfide elicits an anti-inflammatory phenotype in postischemic murine small intestine: role of heme oxygenase-1.

We recently demonstrated that preconditioning with an exogenous hydrogen sulfide donor (NaHS-PC) 24 h before ischemia and reperfusion (I/R) causes postcapillary venules to shift to an anti-inflammatory phenotype in C57BL/6J wild-type (WT) mice such that these vessels fail to support increases in postischemic leukocyte rolling (LR) and leukocyte adhesion (LA). The objective of the present study was to determine whether heme oxygenase-1 (HO-1) is a mediator of these anti-inflammatory effects noted during I/R in mice preconditioned with NaHS. Intravital fluorescence microscopy was used to visualize LR and LA in single postcapillary venules of the murine small intestine.

Thrombosis, physical activity, and acute coronary syndromes.

Acute coronary syndromes (ACS) are common, life-threatening cardiac disorders that typically are triggered by rupture or erosion of an atherosclerotic plaque. Platelet deposition and activation of the blood coagulation cascade in response to plaque disruption lead to the formation of a platelet-fibrin thrombus, which can grow rapidly, obstruct coronary blood flow, and cause myocardial ischemia and/or infarction. Several clinical studies have examined the relationship between physical activity and ACS, and numerous preclinical and clinical studies have examined specific effects of sustained physical training and acute physical activity on atherosclerotic plaque rupture, platelet function, and formation and clearance of intravascular fibrin.