Compositional features of the atherosclerotic lesions.

<p>Quantification of (<b>A</b>) macrophage (CD68+ area), (<b>B</b>) vascular smooth muscle cell (SMA+ area) and (<b>C</b>) total collagen (picrosirius red+ area) content. (<b>D</b>) Quantification of the incidence of intraplaque hemorrhage in Pearls’ Prussian blue stained sections. CD: chow diet; HFD: high fat diet; LCCA: left common coronary artery; LRA: left renal artery; IPH: intraplaque hemorrhages.</p

Vulnerability-Index of the lesions in the mouse models of atherosclerotic plaque destabilization.

<p>Vulnerability-Index (VI) was calculated by the relation between analyzed unstable (<i>U</i>) and stable (<i>S</i>) features of the plaque and corrected by the incidence of lesion formation (p, VI_c). Lesions not representing the type II phenotype were scored as zero. SD was not indicated for models with incidence of n = 1 of type II lesions. LCCA: left common coronary artery; LRA: left renal artery; CD: chow diet; HFD: high fat diet. (n = 3–8; p < 0.05, p < 0.01, p < 0.001 with 1-way ANOVA with Bonferroni’s Multiple Comparison test)</p><p>Vulnerability-Index of the lesions in the mouse models of atherosclerotic plaque destabilization.</p

Summary of features of the plaque destabilization models.

<p>• low •• medium ••• high—n/a</p><p>LCCA: left common coronary artery; LRA: left renal artery; CD: chow diet; HFD: high fat diet; VI: Vulnerability-Index; VI_c: corrected Vulnerability-Index; FC: fibrous cap; NC: necrotic core; IPH: intraplaque hemorrhage.</p><p>Summary of features of the plaque destabilization models.</p

Representative carotid cross-sections of studied specimens for the mouse models of atherosclerotic plaque destabilization.

<p>Mice were fed chow diet (CD) or high fat diet (HFD) as indicated. From left to right: LCCA LRA, model based on the combination of partial ligation of LCCA and LRA; LRA Cast, model based on the combined cast placement around LCCA and partial ligation of LRA; LCCA Cast, model based on the partial ligation of LCCA in combination with the cast placement around the LCCA; Cast, model based on cast placement around the LCCA. Red, yellow and green bars represent thrombus, no lesion or atherosclerotic lesion, respectively. Scale bar = 100μm. LCCA: left common carotid artery; LRA: left renal artery; CD: chow diet; HFD: high fat diet.</p

Structural features of the atherosclerotic lesions.

<p>Quantification of (<b>A</b>) intimal area, (<b>B</b>) intima to media ratio, (<b>C</b>) necrotic core size and (<b>D</b>) fibrous cap thickness. Fibrous cap thickness was only measured when necrotic core was present. NC: necrotic core; FC: fibrous cap; CD: chow diet; HFD: high fat diet; LCCA: left common coronary artery; LRA: left renal artery.</p

Schematic diagrams and experimental setups of the mouse models of atherosclerotic plaque destabilization.

<p>(<b>A</b>) Model based on the combined partial ligation of LCCA (left) and LRA (right). (<b>B</b>) Model based on the combination of cast placement around LCCA (left) and partial ligation of LRA (right). (<b>C</b>) Model based on the partial ligation of LCCA in combination with the cast placement around the LCCA. (<b>D</b>) Model based on cast placement around the LCCA. LCCA: left common carotid artery; LRA: left renal artery; LECA: left external carotid artery; LICA: left internal carotid artery; LSTA: left superior thyroid artery; CD: chow diet; HFD: high fat diet; Lig.: ligation.</p

Apolipoprotein Mimetic Peptide Inhibits Neutrophil-Driven Inflammatory Damage via Membrane Remodeling and Suppression of Cell Lysis

Neutrophils are crucial for host defense but are notorious for causing sterile inflammatory damage. Activated neutrophils in inflamed tissue can liberate histone H4, which was recently shown to perpetuate inflammation by permeating membranes via the generation of negative Gaussian curvature (NGC), leading to lytic cell death. Here, we show that it is possible to build peptides or proteins that cancel NGC in membranes and thereby suppress pore formation, and demonstrate that they can inhibit H4 membrane remodeling and thereby reduce histone H4-driven lytic cell death and resultant inflammation. As a demonstration of principle, we use apolipoprotein A-I (apoA-I) mimetic peptide apoMP1. X-ray structural studies and theoretical calculations show that apoMP1 induces nanoscopic positive Gaussian curvature (PGC), which interacts with the NGC induced by the N-terminus of histone H4 (H4n) to inhibit membrane permeation. Interestingly, we show that induction of PGC can inhibit membrane-permeating activity in general and “turn off” diverse membrane-permeating molecules besides H4n. In vitro experiments show an apoMP1 dose-dependent rescue of H4 cytotoxicity. Using a mouse model, we show that tissue accumulation of neutrophils, release of neutrophil extracellular traps (NETs), and extracellular H4 all strongly correlate independently with local tissue cell death in multiple organs, but administration of apoMP1 inhibits histone H4-mediated cytotoxicity and strongly prevents organ tissue damage