RESUMEN
Calcific aortic valve disease (CAVD) is characterized by progressive mineralization of the aortic valve. Lipid infiltration and oxidative stress are the driving forces for the initiation and development of this disease. However, it remains unknown whether oxidized high-density lipoprotein (ox-HDL) plays a role in the mineralization of aortic valve interstitial cells (AVICs). Serum ox-HDL levels were determined in 168 severe CAVD patients and 168 age- and gender-matched non-CAVD controls. Results showed that ox-HDL concentrations were significantly increased in CAVD compared with the control group (131.52 ± 30.96 ng/mL vs. 112.58 ± 32.20 ng/mL, P < 0.001) and were correlated with CAVD severity. Multivariable logistic regression revealed that ox-HDL levels were independently associated with CAVD after adjusting for the incidence of coronary artery disease (CAD) (odds ratio 1.019, 95% CI 1.012-1.027, P < 0.001) or atherosclerotic risk factors (odds ratio 1.027, 95% CI 1.017-1.037, P < 0.001). Chronic ox-HDL stimulation of AVICs increased alkaline phosphatase activity (ALP) and calcium deposits in AVICs in vitro. Mechanistic studies further showed that ox-HDL upregulated several osteogenic factors, including BMP-2, Runx2, and Msx2 expressions in AVICs. This is the first study to demonstrate a relationship between increased ox-HDL concentration and CAVD incidence.
Asunto(s)
Válvula Aórtica/metabolismo , Calcinosis/metabolismo , Enfermedades de las Válvulas Cardíacas/metabolismo , Lipoproteínas HDL/metabolismo , Osteoblastos/metabolismo , Osteogénesis , Anciano , Fosfatasa Alcalina/metabolismo , Válvula Aórtica/patología , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 2/metabolismo , Calcinosis/sangre , Calcinosis/genética , Calcinosis/patología , Estudios de Casos y Controles , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Estudios Transversales , Femenino , Enfermedades de las Válvulas Cardíacas/sangre , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/patología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Lipoproteínas HDL/sangre , Masculino , Persona de Mediana Edad , Osteoblastos/patología , Osteogénesis/genética , Oxidación-Reducción , Transducción de SeñalRESUMEN
BACKGROUND: Cyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear. METHODS AND RESULTS: In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind-limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate-treated mice. Likewise, there were fewer capillaries in the ischemic hind-limb tissue of cyanate-exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube-formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3-kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09±13.08 versus 15.54±9.02 ng/mL, P=0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth. CONCLUSIONS: Impaired angiogenesis induced by cyanate might contribute to poor coronary collateral growth.