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  • The following are the supplementary data related

    2018-11-07

    The following are the supplementary data related to this article.
    Founding Sources This work was supported by research grants from JSPS [Kakenhi 26250019 and 22122004, NEXT program (LS104), Bilateral Open Partnership Joint Research Projects to K.Sa., Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2704) to K.Sa. and JMG-V, Takeda Science Foundation (to K.Sa.), Terumo Foundation for Life Sciences and Arts (to K.Sa. and I.A.) and Grant-in-Aid for Research at Nagoya City University (to K.Sa.)].
    Author Contributions
    Conflict of Interest Statement
    Acknowledgements We thank Dr. M. Yamaguchi for the reporter mice, Drs. T. Shinohara and S. Takashima for the mice, the Mutant Mouse Regional Resource Center (MMRRC) for the DCX-CreERT2 mice, and Drs. I. Miyoshi and A. Saghatelyan for technical support.
    Introduction Atherosclerosis represents the most important cause of morbidity and mortality in developed countries. Intrinsically atherosclerotic vascular disease is an inflammatory condition characterized by aberrant lipid metabolism and a maladapted EAI045 (Libby et al., 2013). Despite the success of lipid-lowering statins, mortality from atherosclerosis-related pathologies remains high and alternative lipid-targeting approaches are being intensely investigated (Rader, 2016). Based on the inverse association of plasma high-density lipoprotein (HDL)-cholesterol levels and cardiovascular events (Assmann et al., 2002) the ‘HDL hypothesis’ was formulated wherein an increase in HDL-cholesterol would lead to reduction in adverse cardiovascular events. While preclinical studies with HDL infusion, apolipoprotein (Apo) A1 overexpression or inhibition of cholesterylester transfer protein resulted in inhibition or regression of atherosclerosis (Badimon et al., 1990; Tangirala et al., 1999; Kühnast et al., 2015), recent randomized clinical trials using HDL-cholesterol-raising drugs were largely disappointing (AIM-HIGH Investigators et al., 2011; Barter et al., 2007; Schwartz et al., 2012) hence challenging the importance of HDL cholesterol levels in cardiovascular disease. In contrast, clinical trials of low-density lipoprotein (LDL) lowering drugs as well as careful studies of human genetics of LDL-cholesterol and their relationship to cardiovascular risk have unequivocally established LDL as a causal risk factor. Recent strategies to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have corroborated the efficacy of LDL lowering therapies, although neurocognitive side effects, parenteral delivery routes and costs question the long-term feasibility of this approach (Sabatine et al., 2015). Thus, alternative LDL-cholesterol lowering strategies may be beneficial to a large cohort of patients with hypercholesterolemia (Rader, 2016). While atherosclerosis-related inflammation is thought to be predominantly macrophage-driven, recent evidence points towards the importance of neutrophils (Drechsler et al., 2010). These stimulate atherosclerotic lesion formation by releasing the granule protein cathelicidin which paves the way for inflammatory monocytes (Döring et al., 2012). The most abundant neutrophil-derived granule proteins, however, are human neutrophil peptides (HNPs) comprising approximately 5% of total neutrophil protein. HNPs are antimicrobial polypeptides which exert various inflammatory effects when released extracellularly (Choi et al., 2012). As an example, HNPs can stimulate macrophage polarization towards an inflammatory phenotype (Soehnlein et al., 2008) or enhance microvascular permeability (Bdeir et al., 2010). On the other hand, HNPs are strongly cationic and hence show promiscuous, charge-dependent interactions. In this context heteromers comprised of CCL5 and HNP1 were recently shown to strongly stimulate recruitment of classical monocytes (Alard et al., 2015). In addition, HNP1 was shown to interact with Lp(a) (Bdeir et al., 1999) but the pathophysiological relevance of such interaction remains unclear. Here, we study the role of HNP1 in hypercholesterolemia-induced atherosclerosis and witness its strongly protective effect. HNP1-dependent atheroprotection related to enhanced hepatic clearance of HNP1-LDL complexes, a mechanism that could be therapeutically targeted by repetitive HNP1 delivery.