Synthetic high-density or reconstituted lipoproteins (sHDL/rHDL) are a novel class of therapeutics being developed for treatment of cardiovascular disease (CVD). Designed to mimic the athero-protective function of endogenous HDL, sHDLs are composed of apolipoprotein A-I (ApoA-I) protein complexed with phospholipids to form 8-10 nm nanodiscs. In clinical trials, rHDL infusions were shown to reduce atheroma volume, improve endothelial function and reduce systemic inflammation in patients. Known as the ;;good” cholesterol, endogenous HDL asserts its athero-protective properties through efflux of cholesterol from atheroma macrophages and maintaining vascular integrity. Given their proven safety in humans, we proposed that optimizing HDL infusion therapies for treatment of vascular dysfunction, specifically in the context of CVD and sepsis, could be an effective and rapidly translatable therapeutic approach. In the first study we investigated the use of sHDL infusions as a potential therapy for sepsis. Given that multiple factors contribute to sepsis, targeting an endogenous factor with multi-protective effects against endothelial dysfunction may present a novel approach for sepsis therapy. Interestingly, we observed that HDL levels were 45% lower in septic patients compared with non-septic patients. To explore the significance of this finding, we tested the efficacy of sHDL in a murine cecal ligation and puncture model of sepsis. sHDL treatment significantly increased plasma HDL-cholesterol levels, improved 7d survival rate by nearly 40%, and decreased plasma BUN, IL-6 and IL-10 levels. In vitro, sHDL neutralized LPS/LTA, suppressed NF-kB signaling and inhibited endothelial activation. Together, our findings suggest that sHDL therapy can be an effective therapy for sepsis.In the second study, we investigated the potential synergetic effect of co-administering sHDL and a liver X receptor (LXR) agonist on atherosclerosis reduction. We hypothesized that synergy could exist due to the abilities of 1) LXR agonists to increase expression of cholesterol transporters ABCA1 and ABCG1 in foam cells, 2) sHDL to act as a functional cholesterol acceptor, and 3) LXR agonist to overcome sHDL-induced reduction of ABCA1/G1 expression. We show that strong dose-dependent reduction in ABCA1/G1 expression after sHDL treatment can be reversed in vitro by co-administering the LXR agonist T0901317 (T1317). In atherosclerotic mice, sHDL + T1317 combination therapy significantly reduced atheroma burden compared to vehicle-treated controls, while neither sHDL nor T1317 alone had a significant effect. Together, we show that synergetic effect of sHDL and LXR could lead to the lowering of minimal effective doses for each therapeutics resulting in reduction of side effects and lowering barriers for clinical translation.Finally, we incorporated sphingosine-1-phosphate (S1P), a potent anti-inflammatory signaling lipid, in sHDL particles to improve endothelial delivery and barrier function. In vitro, S1P-sHDL treatment increased transendothelial electric resistance and induced a dose-dependent release of nitric oxide. Furthermore, S1P-sHDL was able to dampen endothelial activation after inflammatory insult, inhibiting expression of adhesion molecules and IL-6 and IL-8 pro-inflammatory cytokine production. Given these promising data in vitro, S1P-sHDL presents a viable strategy for the delivery of S1P in an HDL-directed manner, warranting further evaluation in vivo for the treatment of endothelial dysfunction. The findings from these studies have allowed us to develop a more comprehensive understanding of the role that HDL plays in inflammation and vascular disease, consequentially enabling us to rationally design sHDL formulations for potential treatment of inflammatory disorders including atherosclerosis and sepsis.
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Optimizing Synthetic High-Density Lipoprotein Compositions for Modulation of Vascular Inflammation
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