Figure 1.

Carton shows the major functional pathways associated with the effects of ozone therapy on CVD.

The major ozone intermediate is 4-HNE, which may hormetically act on compromised arterial functions due to plaque-mediated obstruction (A) or other etiopathogenetic mechanisms involving microcirculation and arterial endothelia (B). In A, plaque-induced inflammation, platelet activation and IHD may worsen the clinical scenario, ultimately leading to AMI, despite the activation of myogenic protective factors, such as NO and endothelin-1. Ozone prevents AMI and AF mainly by inducing the endothelial production of NO and reducing inflammation and innate cell pyroptosis via 4-HNE in mitochondria (not shown). The triggering of eNOS and production of NO can reduce AF biomarkers (FGF-2α, CD40L, P-Sel, βTG, and so on), improving HFrEF and rejuvenating endothelia and myocardial tissue via the induction of EPCs by 4-HNE-induced pleiotropin (B). Red circles: inhibition; green circles: activation. 4-HNE: 4-Hydroxynonenal; AF: atrial fibrillation; AMI: acute myocardial infarction; CAD: coronary artery disease; CVD: cardiovascular disease; eNOS: endothelial nitric oxide synthase; EPC: endothelial progenitor cell; FGF-2α: fibroblast growth factor-2α; HFrEF: heart failure with reduced ejection fraction; IHD: ischemic heart disease; NO: nitric oxide; P-Sel: P-selectin; UPR: unfolded protein response; βTG: β-thromboglobulin.