DNA Methylation Analysis Identifies Novel Epigenetic Loci in Dilated Murine Heart upon Exposure to Volume Overload.
Xingbo XuManar ElkenaniXiaoying TanJara Katharina HainBaolong CuiMoritz SchnelleGerd HasenfussKarl ToischerBelal A MohamedPublished in: International journal of molecular sciences (2023)
Left ventricular (LV) dilatation, a prominent risk factor for heart failure (HF), precedes functional deterioration and is used to stratify patients at risk for arrhythmias and cardiac mortality. Aberrant DNA methylation contributes to maladaptive cardiac remodeling and HF progression following pressure overload and ischemic cardiac insults. However, no study has examined cardiac DNA methylation upon exposure to volume overload (VO) despite being relatively common among HF patients. We carried out global methylome analysis of LV harvested at a decompensated HF stage following exposure to VO induced by aortocaval shunt. VO resulted in pathological cardiac remodeling, characterized by massive LV dilatation and contractile dysfunction at 16 weeks after shunt. Although methylated DNA was not markedly altered globally, 25 differentially methylated promoter regions (DMRs) were identified in shunt vs. sham hearts (20 hypermethylated and 5 hypomethylated regions). The validated hypermethylated loci in Junctophilin-2 ( Jph2 ), Signal peptidase complex subunit 3 ( Spcs3 ), Vesicle-associated membrane protein-associated protein B ( Vapb ), and Inositol polyphosphate multikinase ( Ipmk ) were associated with the respective downregulated expression and were consistently observed in dilated LV early after shunt at 1 week after shunt, before functional deterioration starts to manifest. These hypermethylated loci were also detected peripherally in the blood of the shunt mice. Altogether, we have identified conserved DMRs that could be novel epigenetic biomarkers in dilated LV upon VO exposure.
Keyphrases
- percutaneous coronary intervention
- dna methylation
- left ventricular
- genome wide
- acute myocardial infarction
- acute coronary syndrome
- coronary artery disease
- heart failure
- atrial fibrillation
- pulmonary artery
- gene expression
- ejection fraction
- end stage renal disease
- newly diagnosed
- cardiovascular events
- chronic kidney disease
- acute heart failure
- poor prognosis
- hypertrophic cardiomyopathy
- transcription factor
- aortic stenosis
- randomized controlled trial
- copy number
- circulating tumor
- coronary artery
- adipose tissue
- hepatitis b virus
- oxidative stress
- clinical trial
- genome wide association
- type diabetes
- patient reported outcomes
- smooth muscle
- cardiovascular disease
- patient reported
- protein kinase
- transcatheter aortic valve replacement
- high fat diet induced