title: Increased fibrosis and progression to heart failure in MRL mice following ischemia/reperfusion injury.
abstract: The cardiac regenerative capacity of MRL/MpJ mouse remains a controversy. Although the MRL mouse has been reported to exhibit minimal scarring and subsequent cardiac regeneration after cryoinjury of the right ventricle, multiple studies have been unable to replicate this cardiac regenerative capacity after both cryogenic and coronary ligation cardiac injury. Therefore, we evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice compared to C57 mice, in response to a clinically relevant left ventricular (LV) coronary ligation. Male MRL/MpJ+/+ and C57BL/6 mice underwent left coronary artery ligation followed by reperfusion. Cardiac function was evaluated by echocardiography [LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV mass, wall thickness] at 24 hours post-ischemia and weekly for 13 weeks thereafter. Hearts were also analyzed histologically for individual cardiomyocyte hypertrophy and cardiac fibrosis. Our results show that contrary to prior reports of cardiac regenerations, MRL mice progress to heart failure more rapidly following I/R injury as marked by a significant decrease in LVEF, increase in LVEDV, LV mass, individual myocyte size, and fibrosis in the post-ischemic myocardium. Therefore, we conclude that MRL mice do not exhibit regeneration of the LV or enhanced functional improvement in response to coronary ligation. However, unlike prior studies, we matched initial infarct size in MRL and C57 mice, used high frequency echocardiography, and histological analysis to reach this conclusion. The prospect of cardiac regeneration after ischemia in MRL mice seems to have attenuated interest, given the multiple negative studies and the promise of stem cell cardiac regeneration. However, our novel observation that MRL may possess an impaired compensated hypertrophy response makes the MRL mouse strain an interesting model in the study of cardiac hypertrophy.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Dia
authors.initials: D
authors.lastname: Smiley
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Carreira
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Sheryl E
authors.initials: SE
authors.lastname: Koch
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kelley
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: Jack
authors.initials: J
authors.lastname: Rubinstein
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH; Department of Pharmacology & Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH.
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, College of Medicine, Cincinnati, OH. Electronic address: trantemc@ucmail.uc.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Tranter
mesh_terms: D000818:Animals; D049108:Cell Enlargement; D018450:Disease Progression; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008955:Models, Cardiovascular; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology; D012038:Regeneration; D013234:Stem Cells / Q000473:pathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
keywords: Cardiac regeneration; Hypertrophy; MRL mice; Myocardial infarction