title: Protective role of 5-azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis.
abstract: We examined whether a shift in macrophage phenotype could be therapeutic for myocardial infarction (MI). The mouse macrophage cell line RAW264.7 was stimulated with peptidoglycan (PGN), with or without 5-azacytidine (5AZ) treatment. MI was induced by ligation of the left anterior descending coronary artery in rats, and the rats were divided into two groups; a saline-injection group and a 5AZ-injection group (2.5 mg/kg/day, intraperitoneal injection). LV function was evaluated and immunohistochemical analyses were performed 2 weeks after MI. Cardiac fibrosis was induced by angiotensin II (AngII) infusion with or without 5AZ (5 mg/kg/day) in mice. Nitric oxide was produced by PGN, which was reduced by 77.87% after 5AZ treatment. Both induction of inducible nitric oxide synthase (iNOS) and iNOS promoter activity by PGN were inhibited by 5AZ. Ejection fraction (59.00 ± 8.03% versus 42.52 ± 2.58%), contractility (LV dP/dt-max, 8299.76 ± 411.56 mmHg versus 6610.36 ± 282.37 mmHg) and relaxation indices (LV dP/dt-min, -4661.37 ± 210.73 mmHg versus -4219.50 ± 162.98 mmHg) were improved after 5AZ administration. Cardiac fibrosis in the MI+5AZ was 8.14 ± 1.00%, compared with 14.93 ± 2.98% in the MI group (P < 0.05). Arginase-1(+)CD68(+) macrophages with anti-inflammatory phenotype were predominant in the infarct border zone of the MI+5AZ group, in comparison with the MI group. AngII-induced cardiac fibrosis was also attenuated after 5AZ administration. In cardiac fibroblasts, pro-fibrotic mediators and cell proliferation were increased by AngII, and these increases were attenuated after 5AZ treatment. 5AZ exerts its cardiac protective role through modulation of macrophages and cardiac fibroblasts.
authors.affiliation: Heart Research Center, Chonnam National University Hospital, Gwangju, South Korea.
authors.forename: Yong Sook
authors.initials: YS
authors.lastname: Kim
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Kang
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Kwon
authors.forename: Moon Hwa
authors.initials: MH
authors.lastname: Hong
authors.forename: Hye-Yun
authors.initials: HY
authors.lastname: Jeong
authors.forename: Hae Chang
authors.initials: HC
authors.lastname: Jeong
authors.forename: Myung Ho
authors.initials: MH
authors.lastname: Jeong
authors.forename: Youngkeun
authors.initials: Y
authors.lastname: Ahn
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling
chemical_list: D000964:Antimetabolites, Antineoplastic; D010457:Peptidoglycan; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001374:Azacitidine
keywords: 5-azacytidine; inducible nitric oxide synthase; macrophage; myocardial infarction