Is plasminogen activator inhibitor‐1 a physiological bottleneck bridging major depressive disorder and cardiovascular disease?

Abstract

Major depressive disorder (MDD) is estimated to affect one in twenty people worldwide. MDD is highly comorbid with cardiovascular disease (CVD), itself one of the single largest causes of mortality worldwide. A number of pathological changes observed in MDD are believed to contribute to the development of cardiovascular disease, although no single mechanism has been identified. There are also no biological markers capable of predicting the future risk of developing heart disease in depressed individuals. Plasminogen activator inhibitor-1 (PAI-1) is a prothrombotic plasma protein secreted by endothelial tissue and has long been implicated in CVD. An expanding body of literature has recently implicated it in the pathogenesis of major depressive disorder as well. In this study, we review candidate pathways implicating MDD in CVD and consider how PAI-1 might act as a mediator by which MDD induces CVD development: chiefly through sleep disruption, adiposity, brain-derived neurotrophic factor (BDNF) metabolism, systemic inflammation and hypothalamic-pituitary-adrenal (HPA)-axis dysregulation. As both MDD and CVD are more prevalent in women than in men, and incidence of either condition is dramatically increased during reproductive milestones, we also explore hormonal and sex-specific associations between MDD, PAI-1 and CVD. Of special interest is the role PAI-1 plays in perinatal depression and in cardiovascular complications of pregnancy. Finally, we propose a theoretical model whereby PAI-1 might serve as a useful biomarker for CVD risk in those with depression, and as a potential target for future treatments.

Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

“…Besides its roles in thrombosis and atherosclerosis, other roles related studies were relatively rare. However, studies indicated that PAI-1 is present in increased levels in various disease states (such as some forms of cancer), as well as in obesity and the metabolic syndrome [20-22]. In inflammatory conditions, PAI-1 appears to play a significant role in the progression to fibrosis, which is pathological formation of connective tissues.…”

Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence

“…20 The levels of PAI-1, along with thrombomodulin and fibrinogen, were also significantly elevated in diabetic patients with depression compared to non-depressive patients and controls. 21 Additionally, Savoy et al 22 recently measured elevated PAI-1 levels in MDD patients. It is interesting to contemplate why elevated levels of PAI-1 consistently correlate with the prevalence of depression.…”

Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression

“…In addition, evidence from preclinical and clinical studies suggests that tPA and its inhibitor, PAI-1, are related to stress reaction and depression and are important fibrinolytic components. Therefore, dysfunction of the tPA–plasmin pathway could be a link between MDD and cardiovascular disease [ 83 , 84 ].…”