Coagulation factor XII contributes to renin activation, heart failure progression, and mortality.

Symptomatic heart failure (sHF) with cardiac dysfunction, edema, and mortality are driven by overactivation of the renin-angiotensin-aldosterone system (RAAS). Renin is widely recognized as a key initiator of RAAS function, yet the mechanisms that activate renin remain a mystery. We discovered that activated coagulation factor XII generates active renin in the circulation and is directly linked to pathological activation of the systemic RAAS, development of sHF, and increased mortality.

Differences in Acute Expression of Matrix Metalloproteinases-9, 3, and 2 Related to the Duration of Brain Ischemia and Tissue Plasminogen Activator Treatment in Experimental Stroke.

Matrix metalloproteinases (MMPs) such as MMP-9, 3, and 2 degrade the cellular matrix and are believed to play a crucial role in ischemic stroke. We examined how the duration of ischemia (up to 4 h) and treatment with recombinant tissue plasminogen activator altered the comparative expression of these MMPs in experimental ischemic stroke with reperfusion. Both prolonged ischemia and r-tPA treatment markedly increased MMP-9 expression in the ischemic hemisphere (all < 0.

Correction: Shakil, H.; Saleem, S. Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice. 2013, , 1095-1108.

The authors wish to make the following corrections to this paper: ref [...

Matrix Metalloproteinase-9 Expression is Enhanced by Ischemia and Tissue Plasminogen Activator and Induces Hemorrhage, Disability and Mortality in Experimental Stroke.

Matrix metalloproteinase-9 (MMP-9) degrades collagen and other cellular matrix proteins. After acute ischemic stroke, increased MMP-9 levels are correlated with hemorrhage, lack of reperfusion and stroke severity. Nevertheless, definitive data that MMP-9 itself causes poor outcomes in ischemic stroke are limited.

Alpha2-Antiplasmin: The Devil You Don't Know in Cerebrovascular and Cardiovascular Disease.

Alpha2-antiplasmin (α2AP), the fast-reacting, serine protease inhibitor (serpin) of plasmin, was originally thought to play a key role in protection against uncontrolled, plasmin-mediated proteolysis of coagulation factors and other molecules. However, studies of humans and mice with genetic deficiency of α2AP have expanded our understanding of this serpin, particularly in disease states. Epidemiology studies have shown an association between high α2AP levels and increased risk or poor outcome in cardiovascular diseases.

Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease.

Stroke and vascular dementia are leading causes of morbidity and mortality. Neuroprotective therapies have been proposed but none have proven clinically tolerated and effective. While overstimulation of N-methyl-d-aspartate-type glutamate receptors (NMDARs) is thought to contribute to cerebrovascular insults, the importance of NMDARs in physiological function has made this target, at least in the view of many in 'Big Pharma,' 'undruggable' for this indication.

Prostaglandin I2 IP Receptor Agonist, Beraprost, Prevents Transient Global Cerebral Ischemia Induced Hippocampal CA1 Injury in Aging Mice.

Beraprost sodium is a new stable, orally active Prostaglandin I2 analogue. The aim of this study was to determine the effect of beraprost on cognitive dysfunction and locomotor impairment induced by bilateral common carotid artery occlusion in mice. We investigated the ameliorating effect of beraprost through PGI2 IP receptor by studying neurologic deficit assessment and T-maze testing in young and old male C57Bl/6 wild-type (WT) and IP receptor knockout (IP KO) mice following a 12 min bilateral common carotid artery occlusion (BCCAo) and 7 days of reperfusion.

S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death.

Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions.

Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice.

Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I2 (PGI2). The present study investigated whether the PGI2 IP receptor plays an important role in brain injury after global cerebral ischemia in aged mice.

Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils.

Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression.

Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage.

Interest in histone deacetylase (HDAC)-based therapeutics as a potential treatment for stroke has grown dramatically. The neuroprotection of HDAC inhibition may involve multiple mechanisms, including modulation of transcription factor acetylation independent of histones. The transcription factor Nrf2 has been shown to be protective in stroke as a key regulator of antioxidant-responsive genes.

The PGE2 EP2 receptor and its selective activation are beneficial against ischemic stroke.

Background: The prostaglandin E2 EP2 receptor has been shown to be important in dictating outcomes in various neuroinflammatory disorders. Here, we investigated the importance of the EP2 receptor in short- and long-term ischemic outcomes by subjecting wildtype (WT) and EP2 knockout (EP2-/-) mice to two distinct and complementary stroke models [transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO)] and by using the EP2 receptor agonist ONO-AE1-259-01.

Methods: First, WT and EP2-/- mice were subjected to 90-min tMCAO with a monofilament followed by 4-day reperfusion.

Death-associated protein kinase-mediated cell death modulated by interaction with DANGER.

Death-associated protein kinase (DAPK) is a key player in multiple cell death signaling pathways. We report that DAPK is regulated by DANGER, a partial MAB-21 domain-containing protein. DANGER binds directly to DAPK and inhibits DAPK catalytic activity.

Effects of Pycnogenol and vitamin E on cognitive deficits and oxidative damage induced by intracerebroventricular streptozotocin in rats.

Oxidative stress plays a crucial role in the progression of cognitive decline in Alzheimer's disease (AD). Considerable attention has been focused on increasing the internal antioxidant defenses in response to AD. This study was designed to examine and compare the pretreatment effects of Pycnogenol (PYC) and vitamin E (Vit E) on cognitive deficits and oxidative damage in the hippocampus and cerebral cortex of intracerebroventricular streptozotocin (ICV-STZ)-infused rats.

PGF(2alpha) FP receptor contributes to brain damage following transient focal brain ischemia.

Although some of the COX-2 metabolites and prostaglandins have been implicated in stroke and excitotoxicity, the role of prostaglandin F(2alpha) (PGF(2alpha)) and its FP receptor have not been elucidated in the pathogenesis of ischemic-reperfusion (I/R) brain injury. Here we investigated the FP receptor's contribution in a unilateral middle cerebral artery (MCA) occlusion model of focal cerebral ischemia in mice. The MCA in wild type (WT) and FP knockout (FP(-/-)) C57BL/6 male mice was transiently occluded with a monofilament for 90 min.

Heme-hemopexin complex attenuates neuronal cell death and stroke damage.

Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the pro-oxidant free heme that is released cannot be recycled and must be degraded. The extracellular heme associates with its high-affinity binding protein, hemopexin (HPX). Hemopexin is shown here to be expressed by cortical neurons and it is present in mouse cerebellum, cortex, hippocampus, and striatum.

Reduced acute brain injury in PGE2 EP3 receptor-deficient mice after cerebral ischemia.

Ischemic stroke is one of the leading causes of mortality and morbidity in humans. During brain ischemia and the subsequent reperfusion that occurs with stroke, the generation of the so-called "proinflammatory" prostaglandin E(2) (PGE(2)) increases significantly. Therefore, interest is growing regarding the differential functions of the individual PGE(2) receptors (EP1-4) and their relative contribution to brain damage following ischemic and inflammatory stimuli.

Ginkgo biloba extract neuroprotective action is dependent on heme oxygenase 1 in ischemic reperfusion brain injury.

Background And Purpose: Ginkgo biloba extracts are now prescribed in several countries for their reported health benefits, particularly for medicinal properties in the brain. The standardized Ginkgo extract, EGb761, has been reported to protect neurons against oxidative stress, but the underlying mechanisms are not fully understood.

Methods: To characterize the oral consumption of EGb761 in transient ischemia, we performed the middle cerebral artery occlusion (MCAO) filament model in wild-type and heme oxygenase 1 (HO-1) knockouts.

Oral supplementation of Majun Baladar ameliorates antioxidant enzyme activities in cerebral ischaemic damage.

Majun Baladar (MB), a traditional herbal formulation of the Unani system of medicine, was studied for its efficacy against cerebral ischaemia-induced oxidative damage in hippocampus and associated neurobehavioural deficits. Adult male Wistar rats were divided into four groups. The first group was sham, the second group was ischaemic (MCAO: middle cerebral artery occluded) and the third group was a MB pre-treated ischaemic group (MCAO + MB).

Effects of EP1 receptor on cerebral blood flow in the middle cerebral artery occlusion model of stroke in mice.

The lipid mediator prostaglandin E2 (PGE2) exhibits diverse biologic activity in a variety of tissues. Four PGE2 receptor subtypes (EP1-4) are involved in various physiologic and pathophysiologic conditions, but differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To characterize the role of the EP1 receptor, physiologic parameters (mean arterial blood pressure, pH, blood gases PaO2 and PaCO2, and body temperature), cerebral blood flow (CBF), and neuronal cell death were studied in a middle cerebral artery occlusion model of ischemic stroke in wild-type (WT) and EP1 knockout (EP1-/-) mice.

PGD(2) DP1 receptor protects brain from ischemia-reperfusion injury.

Prostaglandin D(2) is the most abundant prostaglandin in the brain. It has long been described as a modulator of the neuroinflammatory process, but little is known regarding the role of its Galpha(s)-coupled receptor, DP1. Therefore, in this study, the effect of the DP1 receptor on the outcome of cerebral ischemia in wildtype (WT) and DP1 knockout (DP1(-/-)) C57Bl/6 mice was investigated.

Behavioral and histologic neuroprotection of aqueous garlic extract after reversible focal cerebral ischemia.

The objective of the present study was to investigate the effects of aqueous garlic extract (AGE) on neurobehavioral activities, malondialdehyde (MDA) and reduced glutathione (GSH) levels, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and sodium-potassium ATPase (Na(+),K(+)-ATPase) activities, and glutamate and aspartate content in a middle cerebral artery (MCA) occlusion (MCAO) model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 hours using intraluminal 4-0 monofilament, and reperfusion was allowed for 22 hours. MCAO caused significant depletion in GSH and its dependent enzymes (GPx, GR, and GST) and significant elevation of MDA, glutamate, and aspartate.

Protective effects of ethanolic extract of Delphinium denudatum in a rat model of Parkinson's disease.

Parkinson's disease (PD) is one of the major neurodegenerative disorders, and oxidative stress has been implicated in playing an important role in the pathogenesis of the disease. In the present study, we investigated if Delphinium denudatum extract can slow down the neuronal injury in 6-hydroxydopamine (6-OHDA) rat model of Parkinsonism. Rats were treated with 200, 400 and 600 mg/kg body weight (b.