Aging Accelerates Endotoxin-Induced Thrombosis

Abstract

Although older subjects are susceptible to thrombosis under septic conditions, the underlying molecular mechanisms have not been fully elucidated. Since elevated plasminogen activator inhibitor-1 (PAI-1) primarily contributes to endotoxin-induced thrombosis, we first compared the induction of PAI-1 by lipopolysaccharide (LPS) between young and aged mice. The higher induction of PAI-1 antigen and mRNA with increased renal glomerular fibrin deposition was observed in LPS-treated aged mice compared to young mice. In situ hybridization analysis showed that the aging-associated induction of PAI-1 mRNA by LPS was pronounced in hepatocytes and in renal glomerular cells. The increased magnitude of the response of aged mice to lower doses of LPS was observed in terms of renal glomerular fibrin deposition and PAI-1 mRNA induction in the tissues. Furthermore, older PAI-1 deficient mice treated with LPS developed much less fibrin deposition in kidneys. Importantly, a larger induction of receptor molecules for LPS (eg, CD14 and Toll-like receptor 4) was demonstrated in LPS-treated aged mice as compared with young mice. The enhanced LPS signaling in aged mice was also demonstrated by the marked induction of nuclear factor-kappaB in the tissues after endotoxin treatment. As a consequence, increases in an inflammatory cytokine, tumor necrosis factor-alpha, were pronounced in plasma and tissues of LPS-treated aged mice. These results emphasize the key role played by PAI-1 in aging-associated deterioration in this thrombosis model, and suggest that the hyperresponse of PAI-1 gene to LPS results from the enhanced LPS signaling and the subsequent inflammatory response in aged mice.

Overexpression of the Cell Cycle Inhibitor p16 INK4a Promotes a Prothrombotic Phenotype Following Vascular Injury in Mice

“…LPS is known to activate the vascular endothelium and promote the formation of spontaneous thrombi 31–34 . To study the effects of inflammation-induced coagulation, we exposed p16 INK4a transgenic and wild-type mice to low dose LPS.…”

“…These markers are commonly used to measure activation of coagulation (TAT) 47,48 and endothelial activation (PAI-1) 49,50 . Yamamoto et al showed that aged mice had elevated induction of PAI-1 compared to young mice after LPS treatment, suggesting PAI-1 is important in endotoxin-induced thrombosis 31 . Since PAI-1 is both a marker of endothelial cell senescence and a potent fibrinolysis inhibitor, 51 it could also participate in the delayed thrombus resolution seen in p16 INK4a transgenic mice.…”

Restraint stress enhances arterial thrombosisin vivo– role of the sympathetic nervous system

“…Arterial thrombus formation is the critical step in acute cardiovascular events such as myocardial infarction (Ross, 1999), and tissue factor (TF) is a key trigger of thrombus formation in vivo (Steffel et al, 2006). In addition, inflammation and in particular cytokines such as tumor necrosis factor alpha (TNF-α) (Yamamoto et al, 2002) have been proposed as potential mediators of stress related vascular events as have other components of the coagulation cascade as well as platelets (Larsson et al, 1989).…”

The effects of aging on pulmonary oxidative damage, protein nitration, and extracellular superoxide dismutase down-regulation during systemic inflammation

“…More recent analyses estimate that more than 700,000 patients present with sepsis yearly in the United States resulting in 215,000 deaths of which the majority are elderly people [7, 8]. Although age-related dysregulation of the inflammatory response and thrombosis appear to be involved [9-11], the precise mechanisms for the age-dependent vulnerability to sepsis remain unclear.…”