Complementing the effects of ARB and ACEI on HDL capacity
Complementing the effects of ARB and ACEI on HDL capacity to elicit cholesterol efflux, HDL of ARB- and ACEI-treated groups significantly lessened macrophage production of superoxide (Fig 2). As with efflux, there was no difference in this effect between the ARB and ACEI groups. These data are interesting in view of the extensive evidence that CKD potentiates cellular production of superoxide radicals and that the HDL of CKD patients have impaired antioxidant activity , , , , , . Indeed, a prospective study observed that high levels of oxidized HDL are associated with increased CIMT, while the combination of high ox-HDL and high interleukin-6 predicts not only a greater increase in carotid intima-media thickness but also an increased risk for CVD events and CVD-related mortality in MHD patients . In multivariable models adjusting for established clinical and biochemical risk factors, diminished antioxidant properties of PON-1 predicted higher risk of incident long-term adverse cardiovascular events (heart attack, stroke, or death) in patients with CKD . Given the clinical evidence that inhibition of angiotensin II with ARB or ACEI can lessen oxidative stress and reduce CVD events in the general population, and experimental studies showing that ARB can ameliorate CKD-accelerated atherosclerosis, the current findings suggest that ARB/ACEI modulation of HDL-driven mechanisms (cholesterol efflux and anti-oxidant protection) may have beneficial effects in the MHD d ap5 sale . The potentially advantageous effect of both ARB and ACEI on HDL-mediated cholesterol efflux and oxidant stress appears confounded by consequences specific to each treatment. HDL of MHD patients is known to have defective anti-inflammatory function . Neither ARB nor ACEI improved the macrophage inflammatory cytokine response to uremic HDL, and HDL of ACEI-treated group rather potentiated the cytokine response (Fig 3). These findings are interesting in view of the observations that while antagonism of the renin-angiotensin-aldosterone system in the general population has become a cornerstone of evidence-based therapy for protection against cardiovascular morbidity and mortality, this approach in MHD has yielded mixed results , , , , , , , . Our group reported that ARB in combination with other antihypertensives, but not with ACEI, has a beneficial effect on cardiovascular death in MHD patients . In another study, we found that although 7-day treatment with either ARB or ACEI reduced circulating levels of IL-6 and IL-8 in MHD patients, ACEI-treatment increased pro-inflammatory IL-1β and reduced levels of the anti-inflammatory IL-10 . The current study extends those findings with the novel observation that in MHD patients, ACEI but not ARB treatment leads to HDL that amplifies the macrophage proinflammatory cytokine response. In this connection, the recent landmark study in patients with myocardial infarction treated with monoclonal antibody targeting interleukin-1β with canakinumab showed significantly reduced recurrent cardiovascular events compared placebo . Interestingly, we previously reported that interventions with interleukin1 receptor antagonist or IL-1 trap reduced markers of systemic inflammation and oxidative stress and improved endothelial function in CKD patients . In recent studies we show that the anti-inflammatory and anti-oxidative properties of HDL in these CKD patients is improved by treatment with IL-1blockers . Several mechanisms may contribute to the heightened inflammatory response to HDL from ACEI-treated individuals , . We reported that MHD patients treated for one week with ACEI, but not ARB, have increased circulating levels of methylarginine, specifically ADMA . This is notable because loss of anti-inflammatory and anti-oxidant functions of HDL from CKD patients was linked to SDMA through pathways that include Toll-like receptors . In our study, plasma ADMA or SDMA were not significantly affected by treatment with ARB or ACEI. Further, neither ARB nor ACEI affected the ADMA or SDMA content in HDL. Although the TLR2 and TLR4 response to HDL from placebo-treated group tended to increase and reached significance for TLR4 in ACEI-treated group (Fig 4C), there was no statistical difference among the groups (Fig 4B and D). These findings do not support cytokine potentiation occurring through mechanisms involving HDL methylarginine content regulation of TLRs in our MHD population. HDL also carries SAA, which can directly affect the anti-oxidative and anti-inflammatory capacity of the lipoprotein , . In the current study, there were no differences in these levels among the two treatment arms and placebo. These findings suggest that SAA is not responsible for the proinflammatory effects of HDL of ACEI-treated patients, at least based on our small study.