Vulnérabilité cardiaque au stress au cours du remodelage ventriculaire pathologique : rôle de la mitochondrie et du pore de perméabilité transitionnelle (PTP)

The central objective of this doctoral thesis was to investigate the mitochondrial dysfunction that occurs early during the compensated phase of pathological ventricular remodeling and which may play a causal role in the progression to heart failure. Our previous work using a model of chronic volume overload induced by aorto-caval fistula (ACF) in rats WKHA showed that during the ventricular remodeling, mitochondria developed a vulnerability to permeability transition pore  opening (PTP: a key component of cell death signaling) [1]. This was observed at the stage of compensated remodeling in the absence of major mitochondrial dysfunction typically observed in the failing heart. These results led us to suggest that the vulnerability to PTP opening could be a mechanism facilitating the progression of the cardiomyopathy. In our first study of this thesis we have attempted to test this hypothesis by inducing ACF in two strains of rats displaying sharp differences in the propensity to develop heart failure: WKHA strains and Sprague Dawley (SD). Our studies in vitro on isolated organelles and in situ on the whole organ have confirmed that, in the ACF heart, mitochondria develop a vulnerability to PTP opening and activation of mitochondrial cell death when exposed to stresses relevant to the pathology (calcium overload, ischemia-reperfusion [I-R]). However, SD animals compared to WKHA showed a more rapid and pronounced ventricular remodeling and early progression to heart failure, no difference was found between the two groups in terms of mitochondrial dysfunction, suggesting that this is not behind the more rapid progression of the disease in the SD strain, at least in response to volume overload. We subsequently determined, using the same experimental approaches, if this vulnerability was observed in mitochondria of heart disease from other etiology more specifically that associated with Duchenne muscular dystrophy (DMD), a genetic disease caused by a mutation of the protein dystrophin. Our studies (studies 2-4) on young mdx mice (the mouse model of DMD) free of clinical signs of heart disease showed no difference in basal mitochondrial functions. However, as in the model of ACF, the mitochondria of mdx mice heart were significantly more vulnerable to PTP opening when subjected to I-R (study 2). Furthermore, we demonstrated that acute administration of sildenafil to mdx mice abolished the PTP opening and its signaling consequences, markedly reduced of tissue damage and improved functional recovery following I-R (Study 3). We then tested in mdx mice acute administration of SS31, an antioxidant peptide that targets and accumulates in mitochondria. However, no protective effect was observed, suggesting that the buffering of free radicals have a limited utility if the typical perturbations of the calcium homeostasis in this disease are not treated simultaneously (Study 4). Overall, the work done during this thesis show that the vulnerability to PTP opening is a common and early dysfunction that occurs during pathological ventricular remodeling of different etiologies. Moreover, these studies suggest pharmacological intervention strategies targeting this process, whose effectiveness in preventing heart failure needs to be established.

Keyphrases: Coeur, Heart, Mitochondria, Permeability transition pore, Ischemia-reperfusion, Duchenne muscular dystrophy