4 research outputs found
Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation
Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural
remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to
the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF,
suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial
function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila
melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively
induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling,
upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane
potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial
dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone
and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial
dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased
mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium
uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these
results show that conservation of the mitochondrial function protects against tachypacing-induced
cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target
DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD(+) depletion in experimental atrial fibrillation
Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD+), induces further DNA damage and contractile dysfunction. Accordingly, NAD+ replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF
Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk