PTSD as an Endothelial Disease: Insights From COVID-19

Abstract

SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds that of the general and special populations, the virus may predispose to this disorder by directly interfering with the stress-processing pathways. The SARS-CoV-2 interactome has identified several antigens that may disrupt the blood-brain-barrier by inducing premature senescence in many cell types, including the cerebral endothelial cells. This enables the stress molecules, including angiotensin II, endothelin-1 and plasminogen activator inhibitor 1, to aberrantly activate the amygdala, hippocampus, and medial prefrontal cortex, increasing the vulnerability to stress related disorders. This is supported by observing the beneficial effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in both posttraumatic stress disorder and SARS-CoV-2 critical illness. In this narrative review, we take a closer look at the virus-host dialog and its impact on the renin-angiotensin system, mitochondrial fitness, and brain-derived neurotrophic factor. We discuss the role of furin cleaving site, the fibrinolytic system, and Sigma-1 receptor in the pathogenesis of psychological trauma. In other words, learning from the virus, clarify the molecular underpinnings of stress related disorders, and design better therapies for these conditions. In this context, we emphasize new potential treatments, including furin and bromodomains inhibitors.

Keywords: COVID-19; PTSD; SARS-CoV-2; endothelia; lactate; mitochondria.

FIGURE 1

Several SARS-CoV-2 antigens interact directly with host EC proteins, inducing cellular senescence and altering the BBB permeability. Viral hijacking of furin/plasmin by antigen S2 impairs BDNF maturation, increasing PTSD susceptibility. The S1/ACE-2 attachment upregulates ANG II, inducing mitochondrial damage and cellular senescence. Viral ORF9b disrupts mitochondria directly, altering antiviral defenses and cellular metabolism. The SARS-CoV-2 antigen E exploits host epigenetic readers BRD-2 and BRD-4, altering the expression of mitochondrial proteins encoded in the nuclear DNA. Viral antigen NSP6 interacts with Sigma-1 receptors, inducing cellular senescence by an alternative pathway.

FIGURE 2

Under normal circumstances, tPA facilitates conversion of plasminogen to plasmin. PAI-1 is a tPA inhibitor that downregulates plasmin, a protein necessary for BDNF maturation. The SARS-CoV-2 interaction with ACE-2, increases ANG II inducing EC senescence. Senescent ECs upregulate PAI-1, lowering tPA and plasmin levels. SARS-CoV-2 antigen S2 usurps furin and plasmin (not shown), disrupting the conversion of pro-BDNF into BDNF, that in return impairs synaptic plasticity, predisposing to PTSD. Upregulated pro-BDNF increases PTSD vulnerability further.

FIGURE 3

During brain activation and information processing, ISF enters active astrocytes via AQP-4 channels, leaving less fluid in the extracellular space and upregulating lactate (shuttled to neurons). During idle time or slow wave sleep, ISF exits the astrocyte, widening the extracellular space and lowering lactate to facilitate waste clearance. To accomplish their physiological functions, astrocytes require activation by BDNF. Senescent cerebral ECs produce less BDNF, probably leading to astrocyte deactivation and dysfunctional glymphatic clearance.

FIGURE 4

Glycolysis takes place in the cytoplasm where glucose is converted to pyruvate. Under normal circumstances pyruvate enters the mitochondrion and generates ATP via OXPHOS. Damaged mitochondria may be incapable of sustaining OXPHOS, forcing the cell to rely on lactate (generated via LDH). Excess lactate blocks the antiviral MAVS entry into the mitochondrion through the TOM70 pore. SARS-CoV-2 virus targets TOM70 (via ORF-9b), emphasizing the importance of this channel for both antiviral defenses and cellular metabolism.