The writing on the arterial wall: epigenetic control of blood pressure and vascular remodeling
Lloyd D. Harvey, Stephen Y. Chan
Lloyd D. Harvey, Stephen Y. Chan
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Commentary

The writing on the arterial wall: epigenetic control of blood pressure and vascular remodeling

Abstract

Hypertension is a leading cause of morbidity and mortality, with pathologic consequences on multiple end-organ systems. Smooth muscle plasticity and its epigenetic regulation promote disease pathogenesis, but the genetic levers that control such activity are incompletely defined. In this issue of the JCI, Mangum et al. utilized high-density genomic data to define the causal and pathogenic role of a variant at the JMJD3 locus — one that is associated with systolic blood pressure and governs an allele-specific molecular mechanism controlling smooth muscle behavior in hypertension. These findings have clinical implications relevant to patient risk stratification and personalized therapeutics.

Authors

Lloyd D. Harvey, Stephen Y. Chan

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Figure 1

The single nucleotide variant in JMJD3 links SMC pathobiology to vascular disease.

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The single nucleotide variant in JMJD3 links SMC pathobiology to vascula...
(A) Activation of endothelin receptor A results in increased ERK signaling that is further enhanced by the loss of JMJD3. ERK signaling promotes H3K27me3 expression to attenuate SMC gene profiles with resultant cellular dysfunction. Selective endothelin receptor A antagonists or epigenetic modulators may serve as viable agents in reversing or preventing SMC dysfunction. (B) Integration of multiomics technologies can elucidate underlying mechanisms of disease with direct application to clinical outcomes. Further identification of genetic variants will have implications in polygenic risk scores in clinical prognostication. Identified variants can then be further studied at a molecular level, such as in inducible pluripotent stem cells (iPSCs) differentiated into SMCs for nuanced phenotyping. The implications could extend beyond hypertension to other disorders related to SMC dysfunction.