The Journal of Thoracic and Cardiovascular Surgery

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The Journal of Thoracic and Cardiovascular Surgery The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high- mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway Yikui Tian, MD, Eric J. Charles, MD, Zhen Yan, MD, Di Wu, MS, Brent A. French, PhD, Irving L. Kron, MD, Zequan Yang, MD The Journal of Thoracic and Cardiovascular Surgery DOI: 10.1016/j.jtcvs.2018.09.043 Copyright © 2018 Terms and Conditions

The Journal of Thoracic and Cardiovascular Surgery DOI: (10. 1016/j The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 1 A, Role of high-mobility group box 1 (HMGB1) or cell-free DNA (cfDNA) in myocardial ischemia-reperfusion injury (IRI). C57BL/6 mice underwent 40 minutes of ischemia and 60 minutes of reperfusion. Phatho blue (Heucotech, Fairless Hill, Pa) was used to stain the heart for delineation of infarct size (% of risk region), ischemic risk region (% of left ventricle). Anti-HMGB1 monoclonal antibody at a dose of 1 μg/g mouse weight or dioxyribonuclease I (DNase I) at a dose of 30 mU/g mouse weight administered 5 minutes before the onset of reperfusion. B, Effect of cfDNA depletion on plasma HMGB1. C, Effect of protein depletion on plasma cfDNA. NS, Not significant; PBS, phosphate buffered saline. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 2 Levels of free high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA) in myocardial tissue during ischemia/reperfusion (I/R) injury. C57BL/6 mice underwent either sham thoracotomy or I/R. Sytox green (Thermo Fisher, Waltham, Mass) was injected via intravenous bolus at a dose of 50 μL 1 mM 1 minute before reperfusion. The heart was harvested after injection in sham mice, and 5 minutes, 15 minutes, or 30 minutes following reperfusion. The left ventricle was cut into nonischemic posterior wall and ischemic anterior wall. A, Fluorescence of left ventricle anterior and posterior walls imaged under IVIS Lumina Imaging System (PerkinElmer, Akron, Ohio). B, Levels of cfDNA in the homogenates of the left ventricle anterior and posterior wall were measured using photometer. C, cfDNA was extracted from the left ventricle posterior and anterior walls, respectively, in sham, 40′/5′, and 40′/15′ hearts. The cfDNA was quantitatively measured using Nanodrop 2000 Spectrophotometer (Thermo Fisher Scientific, Waltham, Mass). The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 3 Level of free high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA) in coronary perfusate and plasma during ischemia-reperfusion injury (IRI). Left column, Cardiac coronary perfusate was obtained by antegrade perfusing of the heart via catheter through the ascending aorta. In the perfusate, the level of HMGB1 was measured by Western blot and the level of cfDNA was measured using Sytox Green (Thermo Fisher, Waltham, Mass) and photometry. Right column, The blood sample was obtained during IR by puncturing the right ventricle. The plasma level of HMGB1 was measured by Western blot and the level of cfDNA was measured using Sytox green and photometry. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 4 Role of exogenous cardiac coronary perfusate in exacerbating myocardial infarct size. Perfusate acquired from 10′/0′ or 40′/0′ donor hearts was administered via intravenous bolus 5 minutes before reperfusion at a dose of 2 μL/g recipient mouse. The recipient mice underwent 20′/60′ ischemia-reperfusion (IR). SPLX, Splenectomy 5 minutes before occlusion of left coronary artery. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 5 Role of exogenous plasma in exacerbating myocardial infarct size. A, Plasma acquired from 10′/5′ or 40′/5′ donor C57BL/6 mice was administered intravenous bolus 5 minutes before reperfusion at a dose of 2 μL/g recipient mouse. The recipient mice underwent 20′/60′ ischemia-reperfusion (IR). Immunoprecipitation was used to deplete high-mobility group box 1 (HMGB1) in the donor plasma; deoxyribonuclease I (DNase I) was used to deplete cell-free DNA in the donor plasma at a dose of 1 mU/μL donor plasma. Upper portion, Representative triphenyltetrazolium chloride/Phthalo blue staining of the middle left ventricular slice. Top, the ischemic area (red), infarct area (yellow), and nonischemic area (blue) are drawn and included area can be calculated. B, Level of cell-free DNA in the 40′/5′ plasma with different treatments using Sytox Green (Thermo Fisher, Waltham, Mass). (Results of proteinase K-treated plasma are also reported in Figure 1, C). RAGE KO, Receptor for advanced glycation end products knockout; TLR9 KO, Toll-like receptor 9 knockout. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 6 Splenic tissue level of interleukin (IL)-1β protein and messenger RNA. Spleen was harvested from sham, 10′/30′, and 40′/30′ mice and homogenized. IL-1β protein and messenger RNA were evaluated by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction, respectively. PBS, Phosphate buffered saline; RTC-PCR, reverse transcriptase-polymerase chain reaction. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 7 Role of exogenous recombinant high-mobility group box 1 (rHMGB1) and mitochondrial DNA (mtDNA) in exacerbating myocardial infarct size. C57BL/6 mice and receptor for advanced glycation end products knockout (RAGE KO) mice underwent 20′/60′ ischemia reperfusion (IR) injury and were treated upon reperfusion with either mouse rHMGB1 at a dose of 0.1 μg/g mouse weight and/or mouse mtDNA at a dose of 0.5 μg/g mouse weight. A, Combined treatments 5 minutes before reperfusion exacerbated infarct size in C57BL/6 mice but not in RAGE KO or splenectomized C57BL/6 mice. B, 30 minutes after treatment in mice without IR injury, combined treatments increased splenic tissue DNA level in C57BL/6 mice more significantly than combined treatment in RAGE KO mice or the individual treatment with either rHMGB1 or mtDNA in C57BL/6 mice. C, 30 minutes after treatment in mice without IR injury, the plasma level of cfDNA was similar among the 5 groups. SPLX, Splenectomy 5 minutes before occlusion of left coronary artery; PBS, phosphate buffered saline. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure 8 Schematic mechanism of the free high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA) complex in acute myocardial ischemia-reperfusion injury. DNase I, Deoxyribonuclease I; RAGE, receptor for advanced glycation end products; TLR9, Toll-like receptor 9. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure E1 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; DNase I, deoxyribonuclease I; anti-HMGB1, anti-high-mobility group box 1. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure E2 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; SPLX, splenectomy. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure E3 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; B6, C57BL/6; HMGB1, high-mobility group box 1; DNase I, deoxyribonuclease I; RAGE KO, receptor for advanced glycation end products knockout; TLR9 KO, Toll-like receptor 9 knockout. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure E4 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; PBS, phosphate buffered saline; rHMGB1, recombinant high-mobility group box 1; mtDNA, mitochondrial DNA; SPLX, splenectomy; RAGE KO, receptor for advanced glycation end products knockout. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure E5 Intravenous injection of deoxyribonuclease I (DNase I) at 30 mU/g reduced myocardial infarct size after 40′/60′ ischemia/reperfusion. Lower dose of DNase I (2 mU/g) had no infarct-sparing effect. NS, not significant. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Figure E6 Plasma cell-free DNA (cfDNA) significantly increased after exogenous mitrochondrial DNA injection (0.5 μg/g) at 5 minutes. At 30 minutes, plasma cfDNA decreased back to the normal level. PBS, Phosphate buffered saline. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions

Schematic mechanism of the HMGB1-cfDNA complex in acute myocardial ischemia/reperfusion injury. The Journal of Thoracic and Cardiovascular Surgery DOI: (10.1016/j.jtcvs.2018.09.043) Copyright © 2018 Terms and Conditions