Table 2.
Mechanisms of BRD4 implicated in aging-related diseases.
| Diseases | Functions (BRD4 inhibition) | Study tools | Potential mechanisms | Ref |
|---|---|---|---|---|
| Alzheimer’s disease | Alleviates Alzheimer’s disease | JQ1 | Improves spatial memory via CREB signaling and upregulating synaptic proteins of PSD95 and synaptophysin | [104] |
| JQ1, Genetic (siRNA) inhibition of BET proteins | Decreases the expression of a subset of phagocytosis-related genes and reduced the expression of Cd33, Trem2, and Zyx | [105] | ||
| JQ1 | Partly via downregulation of TNF-α and activation of CREB signaling | [106] | ||
| JQ1 | Elicits gene expression associated with ion channel activity, transcription and DNA repair | [107] | ||
| Exacerbates Alzheimer’s disease | JQ1, ARV-825 | Increases the levels of BACE1 | [108] | |
| Ischemic cerebrovascular diseases | Alleviates ischemic cerebrovascular diseases | dBET1, JQ1 | Inhibits inflammation | [110], [113] |
| Hypertension | Decreases blood pressure | JQ1 | Inhibits VSMC phenotype transition from contractile to synthetic state | [118] |
| Reduces oxidative stress and inflammatory response, alleviates endothelial cell damage, ameliorates aortic injury | [120] | |||
| Neointima formation | Inhibits neointima formation | JQ1 | Inhibits VSMC proliferation | [126], [127], [128] |
| Atherosclerosis | Alleviates atherosclerosis | JQ1 | Inhibits VSMC proliferation, migration, and calcification | [133], [134] |
| JQ-1, I-BET762, RVX-208 |
Regulates macrophage function | [65], [73], [91], [134] | ||
| JQ1, RVX-208 | Alleviates endothelial inflammation | [73], [135], [136], [137] | ||
| RVX-208 | Inhibits synthesis of apolipoprotein A-I | [138] | ||
| Heart failure | Alleviates heart failure | JQ1 | Inhibits the hypertrophic response of cardiac myocytes triggered by extracellular growth cues | [139], [140] |
| JQ1 | Inhibits fibrosis and inflammation | [141], [142], [143], [144] | ||
| Exacerbates heart failure | IBET 151, BRD4-specific knockout in cardiomyocyte | Damages mitochondria function | [98], [99], [145] | |
| Pulmonary fibrosis | Alleviates pulmonary fibrosis | BET inhibitors (IBET, JQ1, CG223, ZL0591, ZL0420 and ZL0454, OTX015) |
Decreases profibrotic gene Nox4 expression | [157], [159] |
| IVDD | Alleviates IVDD | JQ1 | Suppresses MAPK and NF-kB signaling pathways | [86] |
| JQ1 | Induces autophagy Prevents NP cell senescence and apoptosis |
[51], [86] |
CREB: cAMP response element binding protein; PSD95: postsynaptic density protein 95; VSMC: vascular smooth muscle cell; IVDD: intervertebral disc degeneration; NP: nucleus pulposus.