METHODS: A cross-sectional observational study was designed. Forty normotensive (median age 47 +/- 6 yrs.) and twenty untreated hypertensive Malay men (median age 50 +/- 7 yrs.) without clinical evidence of cardiovascular complications were selected. Pulse wave velocity measured using the automated Complior machine was used as an index of arterial stiffness. Other measurements obtained were blood pressure, body mass index, fasting insulin, cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, glucose and creatinine level.
RESULTS: The blood pressure and pulse wave velocity (PWV) were significantly higher in the hypertensives compared to the normotensives (blood pressure 169/100 mm Hg +/- 14/7 vs. 120/80 mm Hg +/- 10/4, p < 0.001; PWV 11.69 m/s +/- 1.12 vs. 8.83 m/s +/- 1.35, p < 0.001). Other variables such as body mass index, fasting insulin, cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and haematocrit were comparable among the two groups. Within each group, there was a significant positive correlation between pulse wave velocity and systolic blood pressure (r = 0.76, p < 0.001 in normotensives; r = 0.73, p < 0.001 in hypertensives) and mean arterial pressure (r = 0.74, p < 0.001 in normotensives; r = 0.73, p < 0.001 in hypertensives). No correlation was noted between pulse wave velocity and diastolic blood pressure, age, body mass index, fasting insulin level, cholesterol, HDL-cholesterol, LDL-cholesterol or triglyceride levels.
CONCLUSION: Arterial stiffness as determined by PWV is increased in newly diagnosed untreated hypertensive subjects even before clinically evident cardiovascular disease. However, arterial stiffness is not correlated with the fasting insulin level in normotensives and newly diagnosed hypertensives.
METHODS: Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)- or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs).
RESULTS: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation.
CONCLUSION: In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.