Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice.

Rationale: Extracellular proteolytic activity plays an important role in memory formation and the preservation of cognitive function. Previous studies have shown increased levels of plasminogen activator inhibitor-1 (PAI-1) in the brain of mouse models of Alzheimer's disease (AD) and plasma of AD patients, associated with memory and cognitive decline; however, the exact function of PAI-1 in AD onset and progression is largely unclear.

Objective: In this study, we evaluated a novel PAI-1 inhibitor, TM5A15, on its ability to prevent or reverse memory deficits and decrease Aβ levels and plaque deposition in APP/PS1 mice.

Associations between GrimAge acceleration and pulmonary function in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

The objective of this research was to determine whether pulmonary function is associated with epigenetic aging (GrimAge) and whether GrimAge predicts emphysema. This prospective study examined 1042 participants enrolled as part of a community-based longitudinal cohort. The cross-sectional associations between pulmonary function and GrimAge, measured at study year (Y) 20 (participant ages 40-45 years), and prospective associations with emphysema at Y25 were examined.

Inequalities in urban greenness and epigenetic aging: Different associations by race and neighborhood socioeconomic status.

Slower epigenetic aging is associated with exposure to green space (greenness); however, the longitudinal relationship has not been well studied, particularly in minority groups. We investigated the association between 20-year exposure to greenness [Normalized Difference Vegetation Index (NDVI)] and epigenetic aging in a large, biracial (Black/white), U.S.

Cardiomyocyte PAI-1 influences the cardiac transcriptome and limits the extent of cardiac fibrosis in response to left ventricular pressure overload.

Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid-acting inhibitor of endogenous plasminogen activators (uPA and tPA). The global PAI-1 knockout mice (PAI-1KO) develop age-dependent cardiac-selective fibrosis, and young global PAI-1KO mice exhibit augmented susceptibility to developing cardiac fibrosis in response to hypertension. Here, we tested the hypothesis that cardiomyocyte PAI-1 is necessary to provide cardioprotective effects in a left ventricular pressure overload-induced murine model of cardiac hypertrophy and fibrosis using cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) mice.

Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study.

The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging.

Assessment of Virological Contributions to COVID-19 Outcomes in a Longitudinal Cohort of Hospitalized Adults.

Background: While several demographic and clinical correlates of coronavirus disease 2019 (COVID-19) outcome have been identified, their relationship to virological and immunological parameters remains poorly defined.

Methods: To address this, we performed longitudinal collection of nasopharyngeal swabs and blood samples from a cohort of 58 hospitalized adults with COVID-19. Samples were assessed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load, viral genotype, viral diversity, and antibody titer.

Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM.

Numerous studies have established that acute or chronic exposure to environmental pollutants like particulate matter (PM) leads to the development of accelerated aging related pathologies including pulmonary and cardiovascular diseases, and thus air pollution is one of the major global threats to human health. Air pollutant particulate matter 2.5 (PM)-induced cellular dysfunction impairs tissue homeostasis and causes vascular and cardiopulmonary damage.

Inhibition of PAI-1 Promotes Lipolysis and Enhances Weight Loss in Obese Mice.

Objective: This study investigates the therapeutic potential of a small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1), TM5441, in reversing diet-induced obesity in mice.

Methods: Wild-type C57BL/6J mice were fed a high-fat high-sugar (HFHS) diet for 8 weeks to induce obesity. After the first 8 weeks, TM5441 was added to the diet for an additional 8 weeks.

Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is the main physiological inhibitor of plasminogen activators. By interacting with matrix components, including vitronectin (Vn), PAI-1 plays a regulatory role in tissue remodeling, cell migration, and intracellular signaling. Emerging evidence points to a role for PAI-1 in various pathological conditions, including cardiovascular diseases, cancer, and fibrosis.

Identification of Cardiac Fibrosis in Young Adults With a Homozygous Frameshift Variant in SERPINE1.

Importance: Cardiac fibrosis is exceedingly rare in young adults. Identification of genetic variants that cause early-onset cardiomyopathy may inform novel biological pathways. Experimental models and a single case report have linked genetic deficiency of plasminogen activator inhibitor-1 (PAI-1), a downstream target of cardiac transforming growth factor β, with cardiac fibrosis.

Role of PAI-1 in hepatic steatosis and dyslipidemia.

Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism.

Effects of lisinopril treatment on the pathophysiology of PCOS and plasminogen activator inhibitor-1 concentrations in rats.

Research Question: Angiotensin-converting enzyme inhibition results in a significant reduction in plasma concentrations of plasminogen activator inhibitor-1 (PAI-1). What are the effects of lisinopril treatment on PAI-1 concentrations and the morphology and function of the ovaries in the letrozole-induced polycystic ovary syndrome (PCOS) rat model?

Design: This prospective randomized controlled animal study involved female Wistar albino rats. Twelve rats were assigned as controls (group I).

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists.

Association between plasminogen activator inhibitor-1 in young adulthood and nonalcoholic fatty liver disease in midlife: CARDIA.

Background: Prior studies have demonstrated a cross-sectional association between elevated plasminogen activator inhibitor-1 (PAI-1) levels and nonalcoholic fatty liver disease (NAFLD). However, there are no prospective longitudinal assessments of the association between PAI-1 and NAFLD. We aimed to describe the association between PAI-1 levels in early adulthood with NAFLD in midlife.

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells.

Therapeutic strategies that target leukemic stem cells (LSCs) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here, we show that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSCs to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSCs and leads to sustained remission of the disease. We demonstrated for the first time that TGF-β-PAI-1 axis was selectively augmented in CML-LSCs in the bone marrow (BM), whereby protecting CML-LSCs from TKI treatment.

PAI-1 contributes to homocysteine-induced cellular senescence.

Cellular Senescence is associated with organismal aging and related pathologies. Previously, we reported that plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. In this study, we investigate the efficacies of PAI-1 inhibitors in both in vitro and in vivo models of homocysteine (Hcy)-induced cardiovascular aging.

Glycine supplementation extends lifespan of male and female mice.

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program.

Acetyltransferase p300 inhibitor reverses hypertension-induced cardiac fibrosis.

Epigenetic dysregulation plays a crucial role in cardiovascular diseases. Previously, we reported that acetyltransferase p300 (ATp300) inhibitor L002 prevents hypertension-induced cardiac hypertrophy and fibrosis in a murine model. In this short communication, we show that treatment of hypertensive mice with ATp300-specific small molecule inhibitor L002 or C646 reverses hypertension-induced left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction, without reducing elevated blood pressures.

Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice.

Plasminogen activator inhibitor 1 (PAI-1), an essential regulator of fibrinolysis, is increasingly implicated in the pathogenesis of metabolic disorders, such as obesity and nonalcoholic fatty liver disease (NAFLD). Pharmacologic inhibition of PAI-1 is emerging as a highly promising therapeutic strategy for obesity and its sequelae. Given the well-established profibrotic function of PAI-1, we considered whether PAI-1 may serve as a target for antifibrotic therapy in nonalcoholic steatohepatitis (NASH).

A null mutation in protects against biological aging in humans.

Plasminogen activator inhibitor-1 (PAI-1) has been shown to be a key component of the senescence-related secretome and a direct mediator of cellular senescence. In murine models of accelerated aging, genetic deficiency and targeted inhibition of PAI-1 protect against aging-like pathology and prolong life span. However, the role of PAI-1 in human longevity remains unclear.

A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis.

Hypertension-associated end-organ damage commonly leads to cardiac and renal fibrosis. As no effective anti-fibrotic therapy currently exists, the unchecked progression of fibrogenesis manifests as cardio-renal failure and early death. We have previously shown that FATp300-p300 with intrinsic factor acetyltransferase activity-is an essential epigenetic regulator of fibrogenesis, and is elevated in several fibrotic tissues.