H19 is not hypomethylated or upregulated with age or sex in the aortic valves of mice

Abstract

Epigenetic dysregulation of long noncoding RNA H19 was recently found to be associated with calcific aortic valve disease (CAVD) in humans by repressing NOTCH1 transcription. This finding offers a possible epigenetic explanation for the abundance of cases of CAVD that are not explained by any clear genetic mutation. In this study, we examined the effect of age and sex on epigenetic dysregulation of H19 and subsequent aortic stenosis. Cohorts of littermate, wild‐type C57BL/6 mice were studied at developmental ages analogous to human middle age through advanced age. Cardiac and aortic valve function were assessed with M‐mode echocardiography and pulsed wave Doppler ultrasound, respectively. Bisulfite sequencing was used to determine methylation‐based epigenetic regulation of H19, and RT‐PCR was used to determine changes in gene expression profiles. Male mice were found to have higher peak systolic velocities than females, with several of the oldest mice showing signs of early aortic stenosis. The imprinting control region of H19 was not hypomethylated with age, and H19 expression was lower in the aortic valves of older mice than in the youngest group. These results suggest that age‐related upregulation of H19 is not observed in murine aortic valves and that other factors may initiate H19‐related CAVD in humans.

Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts

“…74 Although we obtained our pVICs from castrated male pigs, our hVIC observations corroborate sexual dimorphisms observed in pVICs, suggesting that cellular sex differences exist despite hormone status. AVS mouse models also corroborate sex differences in human disease, 75 indicating that cells and tissues from relevant animal sources may be useful tools for understanding sex-specific AVS progression. Together, our results support the observation that cells and tissues of different sexes have distinct regulatory networks that may give rise to sexually dimorphic phenotypes.…”

miRNA-133 and lncRNA-H19 expressions and their relation to serum levels of PKM2 and TGF-β in patients with systemic sclerosis

“…In the same manner, significantly higher serum expression levels of H19 were observed among patients who developed SSc before 14 years of age ( p = 0.018). This was also seen in mice models where younger mice had a higher average H19 expression than older mice [ 60 ]. Further investigations of these findings seem relevant, particularly with the fact that younger patients with SSc ≤30 years frequently present with more disseminated disease [ 61 , 62 ].…”

Regulation of Notch1 Signalling by Long Non-Coding RNAs in Cancers and Other Health Disorders

“…Hadji et al, reported that increased levels of H19 in CAVD lead to an abnormal mineralisation of the aortic valve [ 124 ]. Reducing NOTCH1 signalling in valve interstitial cells increases the expression of genes such as RUNX2 and BMP2 which play a pro-osteogenic role [ 124 , 145 ]. A similar mechanism of action of H19 has been documented in studies of neurogenesis after ischemic stroke.…”