Investigation of the role of poly-ADP-ribose polymerases on mitochondrial energy signaling pathways in heart failure : biological gender specificities

Heart failure (HF) is a major cause of morbidity and mortality, affecting up to 10% of people  over 70 years old. Mitochondrial dysfunction plays a central role in its pathophysiology, particularly through the dysregulation of the PGC-1α axis, a key regulator of mitochondrial biogenesis, identified as a potential therapeutic target. Activation of AMPK and SIRT1 has shown cardioprotective effects by improving mitochondrial function.

Biological sex also influences HF: younger women are protected by estrogens, but this protection is lost after menopause. The PGC-1α cascade is more disrupted in men, likely due to the presence of an estrogen response element in its promoter. AMPK activation also exhibits sexual dimorphism.

Finally, PARPs, enzymes involved in DNA repair, impact mitochondrial function. PARP1, which competes with SIRT1 for NAD utilization, is a target of AMPK. Its inhibition protects mitochondria in male mouse models, but the role of sexual dimorphism in cardiac tissues remains unexplored.

The aim of this study, carried out by UMR-S 1180 and led by Dr Pauline Gaignard, is to determine whether PARP1 activation and its consequences on energy signalling pathways (AMPK and SIRT1) and mitochondrial function differ according to gender in the context of CI. 

The study will be carried out on newborn rat cardiomyocytes and will aim to analyze PARP activation and NAD levels, the regulation of SIRT1, AMPK and PGC-1a following PARP activation, and finally the analysis of respiratory chain complex activity. These measurements will be made first after induction of DNA damage by an alkylating agent, then in the presence of estradiol and an estrogen receptor antagonist. 

#Heartfailure #Westernblot #Cardiomyocytes #Mitochondria #RTqPCR/span>

Investigation of the role of poly-ADP-ribose polymerases on mitochondrial energy signaling pathways in heart failure : biological gender specificities

Heart failure (HF) is a major cause of morbidity and mortality, affecting up to 10% of people  over 70 years old. Mitochondrial dysfunction plays a central role in its pathophysiology, particularly through the dysregulation of the PGC-1α axis, a key regulator of mitochondrial biogenesis, identified as a potential therapeutic target. Activation of AMPK and SIRT1 has shown cardioprotective effects by improving mitochondrial function.

Biological sex also influences HF: younger women are protected by estrogens, but this protection is lost after menopause. The PGC-1α cascade is more disrupted in men, likely due to the presence of an estrogen response element in its promoter. AMPK activation also exhibits sexual dimorphism.

Finally, PARPs, enzymes involved in DNA repair, impact mitochondrial function. PARP1, which competes with SIRT1 for NAD utilization, is a target of AMPK. Its inhibition protects mitochondria in male mouse models, but the role of sexual dimorphism in cardiac tissues remains unexplored.

The aim of this study, carried out by UMR-S 1180 and led by Dr Pauline Gaignard, is to determine whether PARP1 activation and its consequences on energy signalling pathways (AMPK and SIRT1) and mitochondrial function differ according to gender in the context of CI. 

The study will be carried out on newborn rat cardiomyocytes and will aim to analyze PARP activation and NAD levels, the regulation of SIRT1, AMPK and PGC-1a following PARP activation, and finally the analysis of respiratory chain complex activity. These measurements will be made first after induction of DNA damage by an alkylating agent, then in the presence of estradiol and an estrogen receptor antagonist. 

#Heartfailure #Westernblot #Cardiomyocytes #Mitochondria #RTqPCR/span>

internship supervisor

Pauline GAIGNARD