Abstract 10391: Elevated Plasma Branched-Chain Amino Acids Level Promotes Atherosclerosis Progression by Facilitating Macrophage Polarization Toward M1 Phenotype That Results in the Increase of Inflammation

Abstract

Introduction: Few studies have reported that whether elevated plasma branched-chain amino acids (BCAA) level is causally related to atherosclerosis (AS) and the mechanism involved. Methods: First, the plasma BCAA level of 258 atherosclerotic cardiovascular disease (ASCVD) patients and 188 normal people was measured. Second, plaque volume, stability and inflammation of AS mice were evaluated. Third, we assayed BCAA level, catabolism-promoting genes and inflammation in the circulating monocytes of ASCVD patients and abdominal macrophages of AS mice. Fourth, inflammation and macrophage polarization were evaluated in BCAA catabolic deficient RAW 264.7 cells. Finally, mitochondrial hydrogen peroxide (mtH 2 O 2 ), nuclear H 2 O 2 and High mobility group box 1 (HMGB1) levels in RAW 264.7 cells were measured and RAW 264.7 cells-overexpressing catalase targeted to mitochondria (MCAT), nucleus (NCAT) and HMGB1KD RAW 264.7 cells were built to detect their effect on macrophage polarization. Results: First, we found that plasma BCAA level was an independent risk factor of ASCVD. Second, we also found plasma BCAA level was elevated in AS mice, which led to the increase of plaque volume and instability, as well as inflammation. The growth of plaque instability was characterized by increased macrophage amounts and decreased smooth muscle cells (SMCs) and collagen contents. Conversely, when plasma BCAA level was lowered, the above phenomena could be reversed. Third, elevated plasma BCAA level resulting from BCAA catabolic defect occurred in the monocytes of ASCVD patients and the abdominal macrophages of AS mice, which increased inflammatory response by promoting the polarization of macrophages toward M1 phenotype. Fourth, elevated BCAA level-mediated macrophage polarization toward M1 phenotype was regulated by increasing mtH 2 O 2 level to induce secretion of HMGB1 by increasing nuclear H 2 O 2 level. Finally, the improvement of BCAA catabolism of macrophages alleviated AS progression in mice. Conclusions: Our data demonstrates that elevated plasma BCAA level is an independent risk factor of ASCVD and promotes AS progression, indicating that plasma BCAA level might be a therapeutic target for ASCVD.