Targeting histone deacetylase in cardiac diseases

Lu, Jiao; Qian, Sichong; Sun, Zheng

doi:10.3389/fphys.2024.1405569

Cited by 2 publications

References 81 publications

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Enzyme-independent functions of HDAC3 in the adult heart

Qian,

Zhang,

et al. 2024

Preprint

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The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (Δ33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2β (LAP2β). Tethering LAP2β to the HDAC3 Δ33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity, which has implications for understanding the cardioprotective effects of HDIs.

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Enzyme-independent functions of HDAC3 in the adult heart

Qian,

Zhang,

et al. 2024

Preprint

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Histone Deacetylase (HDAC) Inhibitors as a Novel Therapeutic Option Against Fibrotic and Inflammatory Diseases

Theodoropoulou,

Mantzourani,

Kokotos

2024

Biomolecules

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Histone deacetylases (HDACs) are enzymes that play an essential role in the onset and progression of cancer. As a consequence, a variety of HDAC inhibitors (HDACis) have been developed as potent anticancer agents, several of which have been approved by the FDA for cancer treatment. However, recent accumulated research results have suggested that HDACs are also involved in several other pathophysiological conditions, such as fibrotic, inflammatory, neurodegenerative, and autoimmune diseases. Very recently, the HDAC inhibitor givinostat has been approved by the FDA for an indication beyond cancer: the treatment of Duchenne muscular dystrophy. In recent years, more and more HDACis have been developed as tools to understand the role that HDACs play in various disorders and as a novel therapeutic approach to fight various diseases other than cancer. In the present perspective article, we discuss the development and study of HDACis as anti-fibrotic and anti-inflammatory agents, covering the period from 2020–2024. We envision that the discovery of selective inhibitors targeting specific HDAC isozymes will allow the elucidation of the role of HDACs in various pathological processes and will lead to the development of promising treatments for such diseases.

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Targeting histone deacetylase in cardiac diseases

Cited by 2 publications

References 81 publications

Enzyme-independent functions of HDAC3 in the adult heart

Enzyme-independent functions of HDAC3 in the adult heart

Histone Deacetylase (HDAC) Inhibitors as a Novel Therapeutic Option Against Fibrotic and Inflammatory Diseases

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