Proton pump inhibitors accelerate vascular calcification via COX-2-mediated mitophagy inhibition in chronic kidney disease.

Prolonged use of proton pump inhibitors (PPIs) is associated with increased cardiovascular risks, including vascular calcification (VC). Patients with chronic kidney disease (CKD) are particularly vulnerable to the adverse vascular effects of PPIs. However, the underlying mechanism remains poorly understood. Clinical data from CKD patients treated with PPIs showed a higher incidence of elevated coronary artery calcium scores (adjusted odds ratio = 5.365, 95 % CI: 2.539-11.338, P < 0.001), indicating a link between PPI use and accelerated vascular damage. In CKD rats, omeprazole treatment dose-dependently induced aortic calcification, accompanied by a phenotypic switch of vascular smooth muscle cells (VSMCs) from a contractile to an osteoblastic state. This pathological process was associated with mitochondrial dysfunction and inhibited PINK1/Parkin-mediated mitophagy, as evidenced by reduced TOMM20, LC3B-II, PINK1, and Parkin protein levels, impaired mitochondrial-lysosomal colocalization (MitoTracker Green/LysoTracker Red staining), and swollen mitochondria with fewer mitophagosomes (transmission electron microscopy). Enhancement of mitophagy by rapamycin effectively mitigated omeprazole-induced VC. RNA sequencing identified cyclooxygenase-2 (COX-2) as a key mediator, with omeprazole significantly upregulating its expression. Silencing COX-2 reversed omeprazole-induced mitophagy inhibition and VSMC calcification. Esomeprazole and lansoprazole recapitulated these pro-calcific effects, indicating a class effect. Collectively, PPIs promote VC in CKD by upregulating COX-2, which directly inhibits PINK1/Parkin-related mitophagy. This study provides a novel COX-2-mitophagy axis in PPI-accelerated vascular injury, highlighting a potential therapeutic target for high-risk patients.