Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells.

Introduction: Plasminogen Activator Inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis which is implicated in the pathogenesis of myocardial infarction and metabolic syndrome. The formation of reactive oxygen species (ROS) plays an important role in the pathology of vascular disorders and has been shown to increase PAI-1 expression by endothelial cells. Growing evidence indicates that NADPH oxidase and in particular the constitutively active Nox4-p22(phox) complexes are major sources of ROS in endothelial cells.

S35225 is a direct inhibitor of Plasminogen Activator Inhibitor type-1 activity in the blood.

The increased risk of thrombotic events associated with disease states such as diabetes and hypertension has been correlated with elevated circulating levels of Plasminogen Activator Inhibitor type-1 (PAI-1). In the present study we evaluate the benzothiophene derivative S35225 in comparison with two recently described inhibitors of PAI-1 activity Tiplaxtinin and WAY140312 on a panel of PAI-1 activity assays in vitro and in vivo. In a direct chromogenic assay, S35225 has an IC50 value of 44+/-0.

Reduced brain tissue perfusion in TGF-beta 1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities.

We have studied the functional repercussions of cerebrovascular abnormalities in transgenic mice overexpressing TGF-beta1. These mice develop Alzheimer's disease-like vascular and meningeal alterations without parenchymal degeneration. Autoradiographic cerebral blood flow measurements in 9-month-old TGF-beta1 mice compared to non-transgenic littermates provided evidence of reduced tissue perfusion, most prominent in limbic regions.

The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat.

Left ventricular (LV) remodeling following myocardial infarction (MI) is a complex process involving extracellular matrix degradation and fibrosis. While early remodeling is beneficial, chronic remodeling leads to decompensated heart failure (HF). We assessed the hypothesis that activation of the plasminogen-MMP system is involved in the remodeling of the infarct scar and compared it to the remaining viable myocardium.

[Early left ventricular remodelling following acute coronary accident].

Ventricular remodelling following acute coronary syndromes is both complex and multiform. It is due to the response of the myocardium to the different agressions associated with these syndromes, in particular the ischemia and necrosis downstream of the occluded artery. We must not however neglect the role of the remodelling of the lesions resulting from spontaneous reperfusion or provoked by the cells and tissues associated with coronary microcirculation embolisms and the no-reflow phenomenon.

Transforming growth factor-beta 1 production is correlated with genetically determined ACE expression in congenic rats: a possible link between ACE genotype and diabetic nephropathy.

Genetic background appears to modulate the development of diabetic vascular complications. In particular, polymorphisms in the ACE gene have been associated with diabetic nephropathy and, in some studies, macrovascular complications. However, the links between ACE gene polymorphism and factors implicated in diabetes complications remain unknown.

Pulmonary endothelium as a site of synthesis and storage of interleukin-6 in experimental congestive heart failure.

Background: Pulmonary endothelium is an early upstream hemodynamic target of left ventricular dysfunction. Interleukin 6 (IL-6) is a pro-inflammatory cytokine reported to increase in congestive heart failure (CHF) patients.

Aims: We sought to determine the origin of IL-6, IL-6 receptor (IL-6R) and gp130 in experimental CHF.

Molecular and functional dissection of TGF-beta1-induced cerebrovascular abnormalities in transgenic mice.

Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor-beta1 (TGF-beta1) mRNA levels in the midfrontal gyrus correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities.

Doppler echocardiographic estimation of left ventricular end-diastolic pressure after MI in rats.

The spectral Doppler mitral flow pattern, alone or combined with tissue Doppler mitral annulus velocity, can be used to predict left ventricular (LV) filling pressure in humans, whereas invasive hemodynamic measurements are still required in the rat. This study was undertaken to assess whether LV end-diastolic pressure (LVEDP) can be estimated using Doppler echocardiography in the rat after myocardial infarction (MI). Thirty-seven rats (23 rats with MI after left coronary artery ligation and 14 sham-operated rats) were evaluated 3 mo after surgery with echo-Doppler and invasive hemodynamic measurements.

Scar and pulmonary expression and shedding of ACE in rat myocardial infarction.

We examined the topology of angiotensin-converting enzyme (ACE) mRNA expression, activity, and shedding in myocardial infarction-induced heart failure and sought to elucidate the source of the increased plasma ACE activity in this model. Three months after coronary ligature, lung, scar, and remaining viable left ventricular tissues were analyzed for ACE mRNA expression as well as tissue and solubilized ACE activity. ACE mRNA expression increased in the scar with respect to infarct severity, decreased in the lung, and remained unchanged in the left ventricle.