Cellular remodeling of human right atrial appendage during aging and myocardial infarction

Abstract

Cardiac aging is characterized by cardiomyocyte loss, hypertrophy of the remaining cardiomyocytes and replacement fibrosis, leading to diastolic dysfunction. However, mechanisms involved in age-associated cellular loss such as apoptosis, necroptosis, and/or autophagy, remain controversial but are crucial in age-associated pathologies such as non-insulin dependent diabetes mellitus (NIDD) and atrial fibrillation (AF). The objectives of the present study are to identify the mechanisms involved in cardiomyocytes loss and atrial remodeling during aging. Atrial samples (residues of transection of the right atrial appendage for extracorporeal circulation placement) were collected from patients undergoing coronary artery bypass graft from 36 to 83 years old (yo), with or without history of myocardial infarction (MI), (INSERM IRB authorization n C-19-71). Only patients without NIDD and/or AF were studied ( n = 41). After trabeculae dissection and protein extraction, Beclin-1, RIPK3, pro- and cleaved caspase 3 as well as JNK, ERK, AMPK, P38 MAPK and STAT3 pathways were quantified by western blotting in cytosolic fractions and expressed as normalized densitometric score. Phospho-ERK/ERK and phospho-p38 MAPK levels increased with age (factorial ANOVA; respectively P < 0.001 and P < 0.05) but not with MI. In addition, RIPK3 content increased in samples from patients without MI over 70 yo as compared to patients under 55 yo (1.88 ± 0.23 vs. 0.69 ± 0.27; P < 0.05) and was associated with an activation of JNK pathway (phospho-JNK/JNK level: 2.28 ± 0.98 vs. 0.37 ± 0.09; P < 0.05). In contrast, no significant change was observed for Beclin-1 or caspase 3 levels. In patients with MI over 70 yo, as compared to patients of the same age without MI, Beclin-1 (1.26 ± 0.17 vs. 0.83 ± 0.14, P < 0.05) and phospho-STAT3/STAT3 levels (3.09 ± 0.98 vs. 1.18 ± 0.75; P < 0.05) were increased but surprisingly RIPK3 levels were reduced (1.18 ± 0.19 vs. 1.88 ± 0.23; P < 0.05). The age-associated activation of JNK in atria may lead to the loss of Cx43 protein resulting in impaired conduction and contributing to the increasing risk of AF. In addition, the ERK activation, promoting cell survival, is counterbalanced by activation of p38 MAPK, mediating pro-inflammatory cytokine production, and increased RIPK3 suggesting increased necroptosis, without apoptosis. In patients with MI, the high level of Beclin-1 suggests an upregulation of autophagy.