Increased Plasma YKL-40/Chitinase-3-Like-Protein-1 Is Associated with Endothelial Dysfunction in Obstructive Sleep Apnea

Purpose: Obstructive sleep apnea (OSA) is a common disorder affecting 15-24% of the adults and is associated with increased risk of hypertension and atherosclerosis. The exact mechanisms underlying hypertension in OSA are not entirely clear. YKL-40/Chitinase-3-like protein-1 is a circulating moiety with roles in injury, repair and angiogenesis that is dysregulated in atherosclerosis and a number of other diseases. We sought to determine the role of YKL-40 in endothelial dysfunction and hypertension in OSA. Methods: We studies 23 normotensive OSA (N-OSA) and 14 hypertensive OSA (H-OSA) without diabetes and apparent cardiovascular disease. Endothelial-dependent nitric oxide-mediated vasodilatory capacity was assessed by flow-mediated vasodilation (FMD). YKL-40, vascular endothelial growth factor (VEGF) and the soluble form of VEGF receptor-1 or sFlt-1 were measured in plasma using ELISA methodology. Results: N-OSA subjects aged 49.1 +/- 2.3 years and H-OSA aged 51.3 +/- 1.9 years with BMI 36.1 +/- 1.6 and 37.6 +/- 1.9 kg/m(2), respectively. The apnea-hypopnea index (AHI) was 41 +/- 5 events/hr in N-OSA and 46 +/- 6 in H-OSA with comparable degree of oxygen desaturations during sleep. FMD was markedly impaired in H-OSA (8.3%+/- 0.8) compared to N-OSA (13.2%+/- 0.6, P < 0.0001). Plasma YKL-40 was significantly elevated in H-OSA (55.2 +/- 7.9 ng/ml vs. 35.6 +/- 4.2 ng/ml in N-OSA, P = 0.02) and had an inverse relationship with FMD (r = -0.52, P = 0.013). There was a significant positive correlation between sFlt-1/VEGF, a measure of decreased VEGF availability, and YKL-40 (r = 0.42, P = 0.04). Conclusion: The levels of plasma YKL-40 were elevated in H-OSA group and inversely correlated with the endothelial-dependent vasodilatory capacity whereas there was a positive correlation between sFlt-1/VEGF and YKL-40. These findings suggest that YKL-40 is dysregulated, in part, due to perturbation of VEGF signaling, and may contribute to endothelial dysfunction and hypertension in OSA.