Biomolecular Pathways Linking Preoperative Chronic Stress to Postoperative Cardiovascular Dysfunction in Noncardiac Surgery

Figure 1. Molecular mechanisms of chronic stress-induced glucocorticoid resistance. Left panel: Under normal conditions, cortisol binds the glucocorticoid receptor alpha (GRα), which dimerizes, translocates to the nucleus, and suppresses NF-κB-driven transcription of pro-inflammatory cytokines (TNF-α, IL-6), producing an anti-inflammatory effect. Right panel: Under chronic stress with excess cortisol, three mechanisms impair this pathway: (1) p38 MAPK-mediated phosphorylation of GRα reduces ligand-binding affinity and inhibits interaction with NF-κB p65; (2) upregulation of the co-chaperone FKBP5 impairs GRα nuclear translocation and dimerization; (3) alternative splicing of NR3C1 increases expression of GRβ, which forms transcriptionally inactive heterodimers with GRα. TNF-α further upregulates GRβ expression, creating a self-reinforcing cycle. The net result is failure to suppress NF-κB, leading to sustained pro-inflammatory cytokine production. Encircled numerals (1–3) correspond to the three mechanisms of glucocorticoid resistance described above. Solid arrows indicate direct molecular steps or receptor translocation; dashed arrows indicate signaling or transcriptional regulation;…

Figure 2. Molecular mechanisms of chronic stress-induced endothelial dysfunction and early atherogenesis. Left panel: Under normal conditions, endothelial nitric oxide synthase (eNOS), coupled with its cofactor tetrahydrobiopterin (BH4), converts L-arginine to nitric oxide (NO), which diffuses to vascular smooth muscle to promote vasodilation. Right panel: Chronic stress, through HPA axis dysregulation, elevates cortisol, catecholamines, and pro-inflammatory cytokines (TNF-α, IL-6), which impair endothelial function through three sequential mechanisms: (1) cortisol reduces eNOS mRNA stability and transcription factor GATA binding at the eNOS promoter; (2) glucocorticoids deplete BH4; (3) uncoupled eNOS generates superoxide (O2−) instead of NO, producing oxidative stress and endothelial dysfunction. Simultaneously, glucocorticoids stimulate prepro-endothelin-1 (ET-1) mRNA transcription in smooth muscle, shifting the balance toward vasoconstriction. Endothelial activation leads to upregulation of adhesion molecules (ICAM-1, VCAM-1, MCP-1), promoting monocyte adhesion, macrophage activation, and subendothelial lipid deposition. Encircled numerals (①–③) denote the three sequential mechanisms…

Figure 3. Clinical outcomes of chronic stress and immune dysregulation. Left panel: During acute stress, HPA axis activation produces cortisol, which binds GRα and suppresses NF-κB-driven pro-inflammatory cytokine production (TNF-α, IL-6), exerting an anti-inflammatory effect. Right panel: During chronic stress, persistent cortisol and catecholamine elevation leads to glucocorticoid receptor resistance (see Figure 1), macrophage activation, NK-cell activation, and altered T and B cell proliferation. Catecholamines acting via β-adrenergic receptors shift T-helper balance from Th1 (IFN-γ) toward Th2 (IL-4, IL-5) responses. Unopposed NF-κB activation drives chronic inflammation, contributing to downstream clinical consequences including cardiovascular disease, metabolic syndrome, mental disorders, and increased infection susceptibility. Upward arrows (↑) indicate increased and downward arrows (↓) decreased expression or activity; red arrows correspond to the chronic-stress state and the green downward arrow to cytokine suppression during the acute-stress anti-inflammatory response. Straight black arrows indicate direction of signaling or downstream effect. Green shading denotes the…