Inhibition of histone deacetylase as a treatment for cardiac hypertrophy

Abstract

The present invention provides for methods of treating and preventing cardiac hypertrophy. Class II HDACs, which are known to participate in regulation of chromatin structure and gene expression, have been shown to have beneficial effects on cardiac hypertrophy. Surprisingly, the present invention demonstrates that HDAC inhibitors inhibit cardiac hypertrophy by inhibiting fetal cardiac gene expression and interfering with sarcomeric organization.

Description

[0001] The present invention claims benefit of priority to U.S. Provisional Ser. Nos. 60 / 325,311, filed Sep. 27, 2001, and 60 / 334,041, filed Oct. 31, 2001, the entire contents of which are hereby incorporated by reference without reservation.[0002] The government owns rights in the present invention pursuant to grant number NIH RO1 HL61544 from the National Institutes of Health.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates generally to the fields of developmental biology and molecular biology. More particularly, it concerns gene regulation and cellular physiology in cardiomyocytes. Specifically, the invention relates to the use of HDAC inhibitors to treat cardiac hypertrophy and heart failure. [0005] 2. Description of Related Art [0006] Cardiac hypertrophy in response to an increased workload imposed on the heart is a fundamental adaptive mechanism. It is a specialized process reflecting a quantitative increase in cell size and mas...

AI Technical Summary

Benefits of technology

[0010] Thus, in accordance with the present invention, there is provided a method of treating pathologic cardiac hypertrophy and heart failure comprising (a) identifying a patient having cardiac hypertrophy; and (b) administering to the patient a histone deacetylase inhibitor. Administering may comprise intravenous, oral, transdermal, sustained release, suppository, or sublingual administration. The method may further comprise administering a second therapeutic regimen, such as a beta blocker, an iontrope, diuretic, ACE-I, AII antagonist or Ca-blocker. The second therapeutic regimen may be administered at the same time as the histone deacetylase inhibitor, or either before or after the histone deacetylase inhibitor. The treatment may improve one or more symptoms of cardiac failure such as providing increased exercise capacity, increased blood ejection volume, left ventricular end diastolic pressure, pulmonary capillary wedge pressure, cardiac output, cardiac index, pulmonary artery pressures, left ventricular end systolic and diastolic dimensions, left and right ventricular wall stress, wall tension and wall thickness, quality of life, disease-related morbidity and mortality.

Problems solved by technology

All of these signals activate MEF2 and result in cardiac hypertrophy.

However, it is still not completely understood how the various signal systems exert their effects on MEF2 and modulate its hypertrophic signaling.

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