Inhibition of DNA methylation in newborns reprograms ischemia-sensitive biomarkers resulting in development of a heart ischemia-sensitive phenotype late in life

Adverse environmental stress exposure at critical perinatal stages can alter cardiovascular development, which could persist into adulthood and develop a cardiovascular dysfunctional phenotype late in life. However, the underlying molecular mechanisms remain largely unknown. The present study provided a direct evidence that DNA methylation is a key epigenetic mechanism contributing to the developmental origins of adult cardiovas-cular disease. We hypothesized that DNA hypomethylation at neonatal stage alters gene expression patterns in the heart, leading to development of a cardiac ischemia-sensitive phenotype late in life. To test this hypothesis, a DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) was administered in newborn rats from postnatal day 1-3. Cardiac function and related key genes were measured in 2 -week-and 2-month-old animals, respectively. 5-Aza treatment induced an age-and sex-dependent inhibition of global and gene-specific DNA methylation levels in left ventricles, resulting in a long-lasting growth restriction but an asymmetry increase in the heart-to-body weight ratio. In addition, treatment with 5-Aza enhanced ischemia and reperfusion-induced cardiac dysfunc-tion and injury in adults as compared with the saline controls, which was associated with up-regulations of miRNA-181a and angiotensin II receptor type 1 & 2 gene expressions, but down-regulations of PKC epsilon, Atg5, and GSK3 beta gene expressions in left ventricles. In conclusion, our results provide compelling evidence that neonatal DNA methylation deficiency is a key mechanism contributing to differentially reprogram cardiac gene expression patterns, leading to development of a heart ischemia-sensitive phenotype late in life.