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Rôle de la triadine dans le développement de l'insuffisance cardiaque

Abstract : Heart failure (HF) is a serious public health issue with a growing prevalence in industrialized countries. This syndrome results from several cardiac diseases which begin with an adaptative myocardial remodeling: left ventricular hypertrophy (LVH). In heart, contractility depends on calcium release from sarcoplasmic reticulum (SR). This release is controlled by a macro-molecular complex, composed by ryanodine receptor (RyR2) and its associated regulatory protein junctin (JCN), calsequestrin (CSQ2) and triadin (Trd). During the past years, alterations of this complex by disturbed calcium release outside SR (as « sparks ») was often observed during the development of HF, being associated with LVH, dysfunction and fatal ventricular arrhythmias. Most studies were focused on RyR2 and CSQ2 function but few data are available regarding the role of Trd, considered until now having minor role in cardiac physiopathology. To elucidate its role, we realized 3 cardiac pathological experimental models on mice with triadin gene invalidation (KO Trd): 1- a pressure overload with transversal aorta constriction (TAC) 2-a chronic infusion of catecholamines (Isoproterenol, Iso) with osmotic minipumps and 3- a chronic HF with myocardial infarction (MI). In response to TAC or Iso, KO mice developed a greater LVH compared to wild-type mice. Also, with TAC, KO mice show an eccentric LVH associated with a severe cardiac dysfunction, as compared to wild-type mice. After MI, we observed a greater mortality post-surgery in KO Trd mice. This prevalence may be due to increasing of severe ventricular arrhythmias (ventricular tachycardia, VT) after catecholaminergic stimulation. This observation could be a consequence of increasing number of « sparks », and thus an increased calcium release during diastole. More interestingly, delivery of TRDN gene using AAV9 in KO mice, prevent adverse remodeling and the associated cardiac dysfunction following 28 days TAC surgery. To conclude, this work shows that the lack of triadin accelerate the transition towards heart failure, acting on LVH , contractile dysfunction, and the occurrence of lethal ventricular arrhythmias.
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Submitted on : Monday, February 20, 2017 - 3:23:07 PM
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  • HAL Id : tel-01397501, version 1



Pauline Marck. Rôle de la triadine dans le développement de l'insuffisance cardiaque. Cardiologie et système cardiovasculaire. Université René Descartes - Paris V, 2014. Français. ⟨NNT : 2014PA05S018⟩. ⟨tel-01397501⟩



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