title: Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium.
abstract: After myocardial infarction (MI), adverse remodeling with left ventricular (LV) dilatation is a major determinant of poor outcome. Skeletal myoblast (SkM) implantation improves cardiac function post-MI, although the mechanism is unclear. IL-1 influences post-MI hypertrophy and collagen turnover and is implicated in SkM death after grafting. We hypothesized that SkM expressing secretory IL-1 receptor antagonist (sIL-1ra) at MI border zones would specifically attenuate adverse remodeling and exhibit improved graft cell number. Stable murine male SkM lines (5 x 10(5) cells), expressing or nonexpressing (cont) for sIL-1ra, were implanted into infarct border zones of female nude mice immediately after left coronary artery occlusion. LV ejection fraction (LVEF), end-diastolic diameter, and transmitral peak early/late (E/A) flow velocity ratio were determined by echocardiography. Cardiac myocyte hypertrophy and fibrosis were assessed by morphometry, picrosirius red staining, and hydroxyproline assay. At 3 weeks, cont-SkM-engrafted hearts showed reduced hypertrophy, improved LVEF (55.7 +/- 1.2% vs. MI-only: 40.3 +/- 2.9%), and preserved E/A ratios. sIL-1ra-SkM implantation enhanced these effects (LVEF, 67.0 +/- 2.3%) and significantly attenuated LV dilatation (LV end-diastolic diameter, 4.0 +/- 1.1 mm vs. cont-SkM, 4.5 +/- 1.2 mm vs. MI-only, 4.8 +/- 1.8 mm); this was associated with greater graft numbers, as shown by PCR for male-specific smcy gene. Enzyme zymography showed attenuated matrix metalloproteinase-2 and -9 up-regulation post-MI by either donor SkM type, although infarct-remote zone collagen was reduced only with sIL-1ra-SkM. These results suggest that SkM implantation improves cardiac function post-MI by modulation of adverse remodeling, and that this effect can be significantly enhanced by targeting IL-1 as a key upstream regulator of both adverse remodeling and graft cell death.
authors.affiliation: Cell and Gene Therapy Group, National Heart and Lung Institute, Imperial College Faculty of Medicine, London UB9 6JH, United Kingdom. b.murtuza@imperial.ac.uk
authors.forename: Bari
authors.initials: B
authors.lastname: Murtuza
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Beauchamp
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
authors.forename: Terence A
authors.initials: TA
authors.lastname: Partridge
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D000818:Animals; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D032448:Myoblasts, Skeletal / Q000378:metabolism / Q000637:transplantation*; D009203:Myocardial Infarction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D003094:Collagen; D020782:Matrix Metalloproteinases