Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

Abstract

In response to acute and chronic stresses, the heart frequently undergoes a remodeling process that is accompanied by myocyte hypertrophy, impaired contractility, and pump failure, often culminating in sudden death. The existence of redundant signaling pathways that trigger heart failure poses challenges for therapeutic intervention. Cardiac remodeling is associated with the activation of a pathological gene program that weakens cardiac performance. Thus, targeting the disease process at the level of gene expression represents a potentially powerful therapeutic approach. In this review, we describe strategies for normalizing gene expression in the failing heart with small molecules that control signal transduction pathways directed at transcription factors and associated chromatin-modifying enzymes.

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

“…Specific NFAT inhibitors such as modulatory calcineurin-interacting proteins which restrains calcineurin activity has been used to treat cardiac hypertrophy and failure. 55 NFAT inhibitor (A-285222) inhibits NFAT without affecting calcineurin activity and has no off-target side effects in either primates 56,57 or rodents. 58 Therefore, in PAH, NFAT inhibitors might reverse pulmonary vascular remodeling through their effects on PA-SMCs, and inflammatory cells.…”

“…58 Therefore, in PAH, NFAT inhibitors might reverse pulmonary vascular remodeling through their effects on PA-SMCs, and inflammatory cells. 55 Although the RNAs (small interfering RNA and microRNA) have been demonstrated to be effective in NFAT inhibition in PASMC, the lack of suitable vectors, technical methods of extraction and dosage limit their use in vivo. The small molecular, hydrogen exerts its therapeutic effects on MCT-induced PAH in rats by modulating the STAT3/NFATc2 axis and it exhibits few side effects.…”

Kruppel-like Factors (KLFs) in muscle biology

“…In addition, phenotypic changes in skeletal muscle that occur with vascular insufficiency or chronic heart failure are becoming increasingly recognized as significant component of disease pathobiology [2][3][4]. As such, dissecting the molecular mechanisms that drive dysfunction in these cell types represents fertile ground for the development of novel therapies [5].…”

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…Acetylation homeostasis is a major epigenetic mechanism in cancer development and heart dysfunction [18][19][20], which is tightly regulated by the opposing histone acetyltransferases (HATs) and histone deacetylases (HDACs) [21,22]. Acetylation of histones opens chromatin structure for gene transcription; and acetylation also stabilizes and activates transcription factors for an increased activation of target genes [21].…”