NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model.
Jennifer M PetersonDavid J WangVikram ShettigarSteve R RoofBenjamin D CananNadine BakkarJonathan ShintakuJin-Mo GuSean C LittleNivedita M RatnamPriya LondheLeina LuChristopher E GawJennifer M PetrosinoSandya LiyanarachchiHuating WangPaul M L JanssenJonathan P DavisMark T ZioloSudarshana M SharmaDenis C GuttridgePublished in: Nature communications (2018)
Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-κB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function.
Keyphrases
- duchenne muscular dystrophy
- signaling pathway
- skeletal muscle
- lps induced
- nuclear factor
- transcription factor
- oxidative stress
- genome wide
- heart failure
- pi k akt
- histone deacetylase
- gene expression
- muscular dystrophy
- genome wide identification
- dna damage
- end stage renal disease
- toll like receptor
- multiple sclerosis
- newly diagnosed
- insulin resistance
- type diabetes
- ejection fraction
- risk factors
- metabolic syndrome
- cell proliferation
- atrial fibrillation
- angiotensin ii
- peritoneal dialysis