Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium

• DOI: 10.1073/pnas.0306205101
• Publication Date: 2004-03-23T18:22:39Z
• Authors: Bari Murtuza; Ken Suzuki; George Bou-Gharios; Jonathan R. Beauc...; Ryszard T. Smolenski; Terence A. Partridge; Magdi H. Yacoub
• Keywords: 0301 basic medicine; Reverse Transcriptase Polymerase Chain Reaction; Myoblasts, Skeletal; Myocardium; Sialoglycoproteins; Myocardial Infarction; Receptors, Interleukin-1; Matrix Metalloproteinases; Extracellular Matrix; 3. Good health; Interleukin 1 Receptor Antagonist Protein; Mice; 03 medical and health sciences; Animals; Myocytes, Cardiac; Collagen; Interleukin-1

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 × 105cells), 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-specificsmcygene. 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.