ABSTRACT
We have demonstrated that scar formation after myocardial infarction (MI) is associated with an endogenous pool of CD44(pos)CD45(neg) multipotential mesenchymal stem cells (MSC). MSC differentiate into fibroblasts secreting collagen that forms a scar and mature into myofibroblasts that express alpha smooth muscle actin (α-SMA) that stabilizes the scar. In the aging mouse, cardiac repair after MI is associated with impaired differentiation of MSC; MSC derived from the aged hearts form dysfunctional fibroblasts that deposit less collagen in response to transforming growth factor beta-1 (TGF-ß1) and poorly mature into myofibroblasts. We found in vitro that the defect in myofibroblast maturation can be remedied by AICAR, which activates non-canonical TGF-ß signaling through AMP-activated protein kinase (AMPK). In the present study, we injected aged mice with AICAR and subjected them to 1h occlusion of the left anterior descending artery (LAD) and then reperfusion for up to 30days. AICAR-dependent AMPK signaling led to mobilization of an endogenous CD44(pos)CD45(neg) MSC and its differentiation towards fibroblasts and myofibroblasts in the infarct. This was accompanied by enhanced collagen deposition and collagen fiber maturation in the scar. The AICAR-treated group has demonstrated reduced adverse remodeling as indicated by improved apical end diastolic dimension but no changes in ejection fraction and cardiac output were observed. We concluded that these data indicate the novel, previously not described role of AMPK in the post-MI scar formation. These findings can potentially lead to a new therapeutic strategy for prevention of adverse remodeling in the aging heart.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Aminoimidazole Carboxamide/analogs & derivatives , Cicatrix/metabolism , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Ribonucleotides/pharmacology , Aminoimidazole Carboxamide/administration & dosage , Aminoimidazole Carboxamide/pharmacology , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Male , Mice , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/physiopathology , Myofibroblasts/drug effects , Myofibroblasts/metabolism , Phosphorylation/drug effects , Ribonucleotides/administration & dosage , Ventricular Remodeling/drug effects , Wound Healing/drug effectsABSTRACT
Introducción. La osteopetrosis se presenta por una falla en la apoptosis de los osteoclastos, que producen un hueso altamente calcificado pero con mayor fragilidad. Al acumularse calcio en los espacios de los huesos largos destinados a la hematopoyesis, predomina la hematopoyesis secundaria. Con el tiempo se producen visceromegalias y pancitopenias. Es una enfermedad genética con baja incidencia y poca prevalencia en México. Caso clínico. Se trata de un paciente de sexo femenino de 12 años que inició con dolor en los huesos largos durante su niñez temprana de manera recurrente presentaba múltiples fracturas e infecciones; se mantenía en tratamiento con analgésicos y restricción de calcio. Se le considera como candidata para un trasplante de médula ósea, que no se ha realizado. Conclusiones. La osteopetrosis es una enfermedad poco común y compleja. Actualmente, no existe un tratamiento médico efectivo, por lo que es necesario un abordaje multidisciplinario. El trasplante de médula ósea constituye una alternativa viable para el tratamiento de algunos casos de osteopetrosis severa.
Background. Osteopetrosis represents a lack of apoptosis in osteoclastic activity, producing a highly calcified but fragile bone due to excess of calcium. Excess calcium deposited in the medullary compartment leads to bone expansion, producing a predominant secondary hematopoiesis accompanied by significant visceromegaly and pancytopenia. Osteopetrosis is a genetic disease with a low prevalence and incidence in Mexico. Case report. We report the case of a 12-year-old female who presented with bone pain in the lower extremities at an early age. A radiological diagnosis of ostepetrosis was made, and the condition was complicated by multiple fractures and infections. The patient was treated with dietary modifications and analgesics and was considered to be a candidate for hematopoietic stem-cell transplant. Conclusions. Osteopetrosis is a rare and complex disease without any current effective medical treatment, necessitating a multidisciplinary approach. Hematopoietic stem-cell transplantation offers a promising alternative treatment for certain cases of severe osteopetrosis.
