Involvement of cardiomyocyte apoptosis in myocardial injury of hereditary epileptic rats

Many clinical cases have been reported where epilepsy profoundly influenced the pathophysiological function of the heart; however, the underlying mechanisms were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy to investigate the potential mechanisms of myocardial injury. Cardiac functions were assessed by arrhythmia score, heart rate, heart:body mass ratio, and hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular enddiastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/[dt.sub.max] and -dp/[dt.sub.max]). Catecholamine level was detectedby HPLC. Apoptotic index was estimated by TUNEL assay. The expressions of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal protein kinases (JNK), and p38 were evaluated by Western blot. The results indicated that there existed cardiac dysfunction and cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM rats. Further investigation revealed that apoptosis was mediated by reducing Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were upregulated. Our results suggest that the sympathetic nervous system activation and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats. The mechanisms of apoptosis might be associated with the activation of the mitochondriainitiated and the mitogen-activated protein kinase pathways. Key words: epilepsy, tremor rat, myocardial injury, cardiomyocyte, apoptosis. Plusieurs cas cliniques ou l'epilepsie influencait profondement les fonctions pathophysiologiques du coeur ont ete rapportes; toutefois, les mecanismes sous-jacents n'ont pas ete elucides. Nous avons utilise le rat << tremor >> (TRM) comme modele animal d'epilepsie afin d'examiner les mecanismes potentiellement responsables du dommage myocardique. Les fonctions cardiaques ont ete evaluees par le score d'arythmie, le rythme cardiaque, le rapport du poids du coeur sur le poids corporel, ainsi que par les parametres hemodynamiques, dont le taux maximum d'elevation et de chute de la pression ventriculaire gauche (+dp/[dt.sub.max] et -dp/[dt.sub.max]). Le niveau de catecholamines a ete detecte par HPLC. L'indice d'apoptose a ete estime par un dosage TUNEL. L'expression de Bcl-2, de Bax, de la capspase-3, des kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun NH2-terminal protein kinase) et p38 a ete evaluee par buvardage Western. Les resultats ont revele une dysfonction cardiaque et la presence d'apoptose chez les cardiomyocytes, accompagnees par un accroissement des niveaux de catecholamines chez les rats TRM. Une recherche plus poussee a revele que la reduction de Bcl-2, l'augmentation de Bax et l'activation de la caspase-3 etaient les mediateurs de l'apoptose. Des experiences additionnelles ont demontre que le niveau de P-ERK1/2 etait diminue alors que ceux de P-JNK et de P-p38 etaient accrus. Nos resultats suggerent que l'activation du systeme nerveux sympathique et l'apoptose des cardiomyocytes sont impliques dans le dommage myocardique chez les rats TRM. Les mecanismes d'apoptose pourraient etre associes a l'activation des voies signaletiques issues des mitochondries et des proteines kinases activees par les mitogenes. [Traduit par la Redaction] Mots-cles: epilepsie, rat << tremor >>, dommage myocardique, cardiomyocyte, apoptose.
Introduction Epilepsy is one of the most common neurological disorders. Characterized by recurrent seizures, it affects up to 50 million people worldwide (Carpio and Hauser 2009). Patients with epilepsy have [...]