Faculty Bibliography

Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglyceride levels result primarily from defective clearance. The weak association between low-density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and preclinical evidence of the effect of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored.

OBJECTIVE: Interleukin (IL)-33 has been associated with atopic and inflammatory conditions. IL-33 may be atheroprotective inducing a Th1-to-Th2 immunologic switch. However, the role of IL-33 in cardiovascular disease remains unclear. This study examines the effect of physiological and elevated IL-33 levels in plasma from atopic patients (AP) on cholesterol metabolism in human macrophages as compared to plasma from healthy controls (HC). METHODS: Twenty-five AP and 25 HC were enrolled in this study. Plasma samples were analysed for levels of IL-33, IFN-gamma, TNF-alpha, IL-17alpha, IL-5 and soluble ST2. THP-1 differentiated macrophages were exposed to HC and AP plasma. Expression of proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), was measured using QRT-PCR and immunoblotting techniques. RESULTS: IL-33 was significantly higher in AP plasma: 106.7 +/- 95 pg/mL versus HC plasma (53.4 +/- 23 pg/mL). IL-33 concentration strongly correlated with levels of IFN-gamma (r = 0.85), TNFalpha (r = 0.9) and IL-17alpha (r = 0.94). No significant difference was found in soluble ST2 levels. An important contrast was observed for 27-hydroxylase: normal IL-33 in AP plasma amplified 27-hydroxylase while increased IL-33 suppressed it. Expression of CD36 and SR-A1 was greater in macrophages exposed to plasma with high IL-33, while CXCL16 was higher in cells grown in the presence of plasma with normal IL-33. CONCLUSIONS: Here, we demonstrate that high levels of IL-33 and a high IL-33/soluble ST2 ratio correlates with elevated levels of IFN-gamma, TNF-alpha and IL-17alpha as well as IL-5, demonstrating that IL-33 has pleiotropic effects. However, elevated IL-33 did not significantly impact lipid accumulation in macrophages overall. Given the wide variety of cellular responses regulated by IL-33, further investigation with a larger sample size will allow us to clarify the threshold concentration of IL-33 that leads to optimal cholesterol balance.