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Fetal heart enzyme blockade protects against hypertrophy


US scientists have discovered that inhibiting an embryonic heart developmental enzyme protects against adult cardiac hypertrophy in mice.

The findings could lead to new therapeutic strategies against heart failure, says the team led by Dr Chinmay Trivedi from the University of Pennsylvania in Philadelphia.

The enzyme, histone deacetylase 2 (Hdac2), is expressed principally in the fetal heart, but the researchers have shown that it becomes reactivated in adulthood to promote myocyte enlargement. Inhibition of Hdac2 either with pharmacological blockade or deletion of the Hdac2 gene prevented such myocardial responses to hypertrophic stresses in mice.

“It’s as if old programmes are being reactivated in a sick heart,” explained co-author Professor Jonathan Epstein, also of the University of Pennsylvania. “In an adult heart, stresses such as high blood pressure induce the re-expression of a fetal gene programme.”

Hdac2 acts as a switch in the regulation of DNA packaging into chromatin, and usually regulates myocyte proliferation in the embryo.

Prof Epstein said: “We found that in various mouse models of cardiac hypertrophy and heart failure, treatment with chemical HDAC inhibitors or genetic deletion of Hdac2 prevented the beginning of the downward slide to progressive heart failure.”

More specifically, Hdac2 inhibition or deletion prevented the re-expression of other fetal genes and prevented cardiac hypertrophy in mouse hearts exposed to hypertrophic stimuli, including isoproterenol and transaortic constriction.

This resistance to hypertrophy was associated with increased expression of inositol polyphosphate-5-phosphatase (Inpp5f), resulting in constitutive expression of glycogen synthase kinase 3β. Inhibition of Gsk3β led to Hdac2-deficient mice once more becoming susceptible to hypertrophic stimuli.

“HDAC and Inpp5f give us new targets for regulating cardiac hypertrophy,” said Prof Epstein. “Inhibitors of HDAC may warrant testing for cardiac disease to stop the hypertrophy that accompanies the re-expression of the fetal-gene programme.”

He added that understanding how to better treat heart disease at the cellular level was an important future goal.


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