Is plasminogen activator inhibitor-1 a physiological bottleneck bridging major depressive disorder and cardiovascular
C Savoy1,2, R J Van Lieshout1,2, M Steiner1,2
1Women's Health Concerns Clinic, St. Joseph's Healthcare, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
Insights
Major depressive disorder (MDD) and cardiovascular disease (CVD) are linked. Plasminogen activator inhibitor-1 (PAI-1) may mediate CVD risk in MDD patients, offering a potential biomarker and therapeutic target.
Area of Science:
- Neuroscience
- Cardiology
- Endocrinology
Background:
- Major depressive disorder (MDD) affects 5% of the global population and is highly comorbid with cardiovascular disease (CVD), a leading cause of mortality.
- Current understanding lacks identified mechanisms linking MDD to CVD and predictive biomarkers for CVD risk in depressed individuals.
- Plasminogen activator inhibitor-1 (PAI-1), a prothrombotic protein, is implicated in both CVD pathogenesis and MDD.
Purpose of the Study:
- To review pathways linking MDD to CVD development.
- To explore PAI-1's potential role as a mediator between MDD and CVD.
- To investigate sex-specific and hormonal associations, particularly in perinatal depression and pregnancy-related CVD.
Main Methods:
- Literature review of candidate pathways implicating MDD in CVD.
- Analysis of PAI-1's potential mediating role through sleep disruption, adiposity, BDNF, inflammation, and HPA-axis dysregulation.
- Exploration of hormonal and sex-specific associations, including PAI-1's role in perinatal depression and pregnancy complications.
Main Results:
- Several pathways, including sleep disruption, adiposity, BDNF metabolism, systemic inflammation, and HPA-axis dysregulation, are proposed to link MDD to CVD.
- PAI-1 is suggested as a potential mediator in these pathways.
- Hormonal influences and sex-specific differences, especially concerning PAI-1 in women, perinatal depression, and pregnancy, are highlighted.
Conclusions:
- PAI-1 may serve as a crucial link between MDD and CVD development.
- PAI-1 could be a valuable biomarker for assessing CVD risk in individuals with depression.
- Targeting PAI-1 may offer a novel therapeutic strategy for managing comorbid MDD and CVD.
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.
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