title: Type I collagen cleavage is essential for effective fibrotic repair after myocardial infarction.
abstract: Efficient deposition of type I collagen is fundamental to healing after myocardial infarction. Whether there is also a role for cleavage of type I collagen in infarct healing is unknown. To test this, we undertook coronary artery occlusion in mice with a targeted mutation (Col1a1(r/r)) that yields collagenase-resistant type I collagen. Eleven days after infarction, Col1a1(r/r) mice had a lower mean arterial pressure and peak left ventricular systolic pressure, reduced ventricular systolic function, and worse diastolic function, compared with wild-type littermates. Infarcted Col1a1(r/r) mice also had greater 30-day mortality, larger left ventricular lumens, and thinner infarct walls. Interestingly, the collagen fibril content within infarcts of mutant mice was not increased. However, circular polarization microscopy revealed impaired collagen fibril organization and mechanical testing indicated a predisposition to scar microdisruption. Three-dimensional lattices of collagenase-resistant fibrils underwent cell-mediated contraction, but the fibrils did not organize into birefringent collagen bundles. In addition, time-lapse microscopy revealed that, although cells migrated smoothly on wild-type collagen fibrils, crawling and repositioning on collagenase-resistant collagen was impaired. We conclude that type I collagen cleavage is required for efficient healing of myocardial infarcts and is critical for both dynamic positioning of collagen-producing cells and hierarchical assembly of collagen fibrils. This seemingly paradoxical requirement for collagen cleavage in fibrotic repair should be considered when designing potential strategies to inhibit matrix degradation in cardiac disease.
authors: Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors: Zengxuan
authors: Z
authors: Nong
authors: Caroline
authors: C
authors: O'Neil
authors: Ming
authors: M
authors: Lei
authors: Robert
authors: R
authors: Gros
authors: Alanna
authors: A
authors: Watson
authors: Amin
authors: A
authors: Rizkalla
authors: Kibret
authors: K
authors: Mequanint
authors: Shaohua
authors: S
authors: Li
authors: Matthew J
authors: MJ
authors: Frontini
authors: Qingping
authors: Q
authors: Feng
authors: J Geoffrey
authors: JG
authors: Pickering
mesh_terms: D000818:Animals; D002465:Cell Movement; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D017364:Collagenases / Q000235:genetics / Q000502:physiology*; D003250:Constriction; D003331:Coronary Vessels; D005347:Fibroblasts / Q000201:enzymology* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009203:Myocardial Infarction / Q000201:enzymology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D017364:Collagenases