RESUMEN
AIMS: Our objective was to study the effect of the genetic background on the wound healing process after myocardial infarction (MI) in mice. METHODS AND RESULTS: MI was induced in five different mouse strains (BalbC, C57Bl6, FVB, 129S6, and Swiss). At 3, 14, and 28 days after MI, cardiac dimensions were monitored by echocardiography and histology, whereas cardiac function was determined by direct intraventricular pressure measurements (dP/dt). Furthermore, matrix metalloproteinases were measured by zymography, and mRNA expression by quantitative PCR. Infarct rupture, which typically occurred at 3-6 days post-MI, was most frequent in 129S6 mice (62%), followed by C57Bl6 (36%), FVB (29%), Swiss (23%), and BalbC (5%). The high incidence of infarct rupture in 129S6 mice was associated with high systolic blood pressure and increased influx of inflammatory cells. Cardiac dilatation was most marked in Swiss mice and least prominent in 129S6 mice. The degree of dilatation was associated with a reduced ejection fraction and decreased dP/dt values at 14 and 28 days post-MI. At day 14 and 28 post-MI, secondary thinning of the infarct area was marked in BalbC, FVB, and Swiss, but absent in C57Bl6 and 129S6 mice. In the latter two groups, this was paralleled by the highest number of myofibroblasts at day 14 post-MI. CONCLUSION: The outcome of infarct healing in mice strongly depends on genetic background. On the basis of our results, we suggest that for studies on infarct rupture, the 129S6 mouse is the background of choice, whereas BalbC and Swiss mice are the preferred models to study infarct thinning post-MI.
Asunto(s)
Rotura Cardíaca Posinfarto/genética , Infarto del Miocardio/genética , Miocardio/patología , Cicatrización de Heridas/genética , Animales , Antihipertensivos/farmacología , Factor Natriurético Atrial/genética , Presión Sanguínea/genética , Modelos Animales de Enfermedad , Ecocardiografía , Regulación Enzimológica de la Expresión Génica , Rotura Cardíaca Posinfarto/patología , Rotura Cardíaca Posinfarto/fisiopatología , Rotura Cardíaca Posinfarto/prevención & control , Inflamación/genética , Inflamación/patología , Inflamación/fisiopatología , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/enzimología , Péptido Natriurético Encefálico/genética , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Especificidad de la Especie , Volumen Sistólico/genética , Factores de Tiempo , Función Ventricular Izquierda/genética , Presión Ventricular/genéticaRESUMEN
OBJECTIVES: Our goal was to evaluate intercellular adhesion complex proteins in myocardium in human infarct rupture. BACKGROUND: Infarct rupture, a fatal complication of myocardial infarction (MI), has been attributed to a defective cell adhesion complex in a transgenic mouse model. METHODS: Heart samples were collected from autopsies from infarct rupture and control (nonrupture) MI patients. Both infarcted and remote areas were included. Cell adhesion proteins including alphaE-catenin, beta-catenin, gamma-catenin, and N-cadherin were characterized by immunohistochemistry and immunoblotting. Genetic analysis was undertaken to evaluate mutations and polymorphisms in the alphaE-catenin gene. In addition, infarct rupture was studied in transgenic mice heterozygous for alphaE-catenin C-terminal deficiency, mimicking the situation in human infarct rupture patients. RESULTS: No alphaE-catenin was detected in 70% of remote samples of infarct rupture hearts compared with 20% in control MI by immunohistochemistry. The immunoblot analysis confirmed a significant reduction in remote areas, and complete absence of alphaE-catenin in infarct areas from infarct rupture patients. No mutation or polymorphism of the alphaE-catenin gene was discovered. Other cell adhesion proteins were not significantly affected in remote areas of infarct rupture hearts. Three-fourths of the heterozygous alphaE-catenin C-terminal truncated mice died of infarct rupture, compared with one-fourth of the wild-type littermates. CONCLUSIONS: The data show a reduced expression and defective localization of alphaE-catenin in the intercalated disc region in patients dying of infarct rupture. The mechanism of lower expression of alphaE-catenin remains to be elucidated.
