title: Controlled release of ascorbic acid from gelatin hydrogel attenuates abdominal aortic aneurysm formation in rat experimental abdominal aortic aneurysm model.
abstract: OBJECTIVE
  Abdominal aortic aneurysms (AAAs) are associated with oxidative stress and inflammatory response. We investigated the hypothesis that the known antioxidant ascorbic acid, which can also promote elastin and collagen production by smooth muscle cells, would prevent AAA formation in a rat model.
  
  
  METHODS
  An intraluminal elastase and extraluminal calcium chloride-induced rat AAA model was used, and the animals were divided into three groups: control (group C, n = 18), the aorta wrapped with a saline-impregnated gelatin hydrogel sheet (group G, n = 18), and the aorta wrapped with a gelatin hydrogel sheet incorporating ascorbic acid (group A, n = 18). Wrapping of the sheet was completed at the end of treatment for AAA creation. The aortic dilatation ratio was measured, and aortic tissues were further examined for oxidative stress and oxidative DNA damage using biochemical and histologic techniques.
  
  
  RESULTS
  Aortic dilatation at both 4 and 8 weeks was inhibited in group A (dilatation ratio [%] at 4 weeks: 186.2 ± 21.8 in group C, 152.3 ± 10.2 in group G, 126.8 ± 11.6 in group A; P < .0001; dilatation ratio [%] at 8 weeks: 219.3 ± 37.5 in group C, 194.0 ± 11.6 in group G, 145.7 ± 8.3 in group A; P = .0002). Elastin and collagen content were significantly preserved in group A (elastin, P = .0015; collagen, P < .0001). The messenger RNA expressions of matrix metalloproteinase (MMP)-9, monocyte chemotactic protein-1, interleukin-1β, and tissue necrosis factor-α (P = .0024, P < .0001, P < .0001, and P < .0001, respectively) were downregulated in group A (P = .0024), whereas tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were both upregulated in group A (TIMP-1, P = .0014; TIMP-2, P < .0001). Gelatin zymography showed activities of pro-MMP-2, MMP-2, and MMP-9 were significantly suppressed in group C (P < .0001 for each). Reactive oxygen species expression and 8-hydroxydeoxyguanosine and cluster of differentiation 68 staining were significantly suppressed in group A (reactive oxygen species expression, P < .0001; 8-hydroxydeoxyguanosine-positive cells, P < .0001; cluster of differentiation 68 positive cells, P < .0001).
  
  
  CONCLUSIONS
  Controlled release of ascorbic acid using gelatin hydrogel sheet-attenuated AAA formation through antioxidant and anti-inflammatory effect, regulation of MMP-2, TIMP-1, and TIMP-2, and preserving elastin and collagen in this animal model.
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Wulan
authors.initials: W
authors.lastname: Bao
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okita
authors.affiliation: Department of Biomaterial, Field of Tissue Engineering, Institute for Frontier Medical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: yutamo@aol.com.
authors.forename: Kenji
authors.initials: K
authors.lastname: Okada
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001205:Ascorbic Acid / Q000008:administration & dosage* / Q000737:chemistry; D002122:Calcium Chloride; D002626:Chemistry, Pharmaceutical; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003692:Delayed-Action Preparations; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004337:Drug Carriers; D004549:Elastin / Q000378:metabolism; D005780:Gelatin / Q000737:chemistry*; D005786:Gene Expression Regulation; D020100:Hydrogels; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010196:Pancreatic Elastase; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D012333:RNA, Messenger; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D003094:Collagen; D004549:Elastin; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D002122:Calcium Chloride; D001205:Ascorbic Acid