BACKGROUND

Cardiac hypertrophy is an adaptive response to pressure or volume stress, mutations of sarcomeric (or other) proteins, or loss of contractile mass from prior infarction. Hypertrophic growth accompanies many forms of heart disease, including ischemic disease, hypertension, congestive heart failure, valvular disease and subsequent cardiac death. In these types of cardiac pathology, pressure overload-induced concentric hypertrophy is believed to have a compensatory function by diminishing wall stress and oxygen consumption. At the same time, ventricular hypertrophy is associated with significantly increased risk of heart failure and malignant arrhythmia.

REV-ERBα, also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1) is a transcriptional repressor. REV-ERBα is highly expressed in the liver, skeletal muscle, adipose tissue, and the brain, in mammals, participating in the development and circadian regulation of these tissues. REV-ERBα regulates gene transcription by directly binding to target response elements (RevREs), comprises an A/T-rich flank followed by AGGTCA.

SUMMARY

Embodiments described herein relate to compositions and methods for use in the prevention and treatment of cardiac hypertrophy and heart failure. It was found that pharmacological activation of REV-ERBα selectively suppresses aberrant pathologic gene expression and prevents cardiomyocyte hypertrophy. In vivo, REV-ERBα activation prevents development of cardiac hypertrophy, reduces fibrosis, and halts progression of advanced heart failure. Accordingly, in some embodiments a method of treating and/or preventing cardiac hypertrophy and/or heart failure in a subject in need thereof includes administering to the subject a therapeutically effective amount of a REV-ERBα agonist.

In some embodiments, the REV-ERBα agonist is selected from the group consisting of 1,1-Dimethylethyl N-[(4-chlorophenyl)methyl]-N-[(5-nitro-2-thienyl)methyl])glycinate (SR6452); N-Benzyl-N-(4-chlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine; N-Benzyl-N-(3,4-dichlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine; 2-((4-chlorobenzyl)((5-nitrothiophen-2-yl)methyl)amino)-N,N-dimethylacetamide, SR9009, SR9011 and pharmaceutically acceptable salts thereof.

