Hdac9-KO Mouse

HDAC9, a histone deacetylase enzyme belonging to the class IIa of HDACs, catalyzes histone deacetylation. It inhibits cell proliferation through DNA repair, cell cycle arrest, apoptosis induction, and genetic expression alteration. HDAC9 is involved in various biological processes and is associated with multiple pathways related to different diseases [4].

In atherosclerotic disease, a variant in the HDAC9 gene is a risk factor. Reducing HDAC9 protein in animal and cellular models is associated with reduced disease, suggesting that inhibiting HDAC9 may be a novel treatment approach [1]. In male mouse kidney fibrosis models, tubule-specific deletion or pharmacological inhibition of HDAC9 alleviates epithelial cell cycle arrest in G2/M, reducing profibrotic cytokine production and tubulointerstitial fibrosis [2]. In intervertebral disc degeneration (IVDD), HDAC9KO mice spontaneously develop age-related IVDD, while overexpression of HDAC9 in NP cells alleviates IVDD symptoms in a surgically-induced mouse model [3]. In vascular calcification models, both pharmacological inhibition and knockdown of HDAC9 attenuated calcification of human vascular smooth muscle cells, while overexpression exacerbated it [5]. In matrix Gla protein-deficient mice (a model of human vascular calcification), mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival [6]. In myocardial infarction models, HDAC9 knockout induced the activation of Nrf2 and protected the heart from injury [7]. In the chronic restraint stress mouse model of depression, knockdown or knockout of HDAC9 in hippocampal neurons alleviated depression-like phenotypes [8].

In conclusion, HDAC9 plays a significant role in multiple biological processes and is involved in various diseases such as atherosclerosis, kidney fibrosis, IVDD, vascular calcification, myocardial infarction, and depression. Gene knockout mouse models have been crucial in revealing its functions in these disease conditions, providing potential therapeutic targets for treatment.

References:

1. Markus, Hugh S. 2023. HDAC9 Inhibition as a Novel Treatment for Stroke. In Stroke, 54, 3182-3189. doi:10.1161/STROKEAHA.123.044862. https://pubmed.ncbi.nlm.nih.gov/37942644/

2. Zhang, Yang, Yang, Yujie, Yang, Fan, Liu, Min, Yi, Fan. 2023. HDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice. In Nature communications, 14, 3007. doi:10.1038/s41467-023-38771-4. https://pubmed.ncbi.nlm.nih.gov/37230975/

3. Lei, Ming, Lin, Hui, Shi, Deyao, Liao, Zhiwei, Yang, Cao. 2023. Molecular mechanism and therapeutic potential of HDAC9 in intervertebral disc degeneration. In Cellular & molecular biology letters, 28, 104. doi:10.1186/s11658-023-00517-x. https://pubmed.ncbi.nlm.nih.gov/38093179/

4. Das, Totan, Khatun, Samima, Jha, Tarun, Gayen, Shovanlal. . HDAC9 as a Privileged Target: Reviewing its Role in Different Diseases and Structure-activity Relationships (SARs) of its Inhibitors. In Mini reviews in medicinal chemistry, 24, 767-784. doi:10.2174/0113895575267301230919165827. https://pubmed.ncbi.nlm.nih.gov/37818566/

5. Lan, Zirong, Chen, An, Li, Li, Lu, Lihe, Yan, Jianyun. 2022. Downregulation of HDAC9 by the ketone metabolite β-hydroxybutyrate suppresses vascular calcification. In The Journal of pathology, 258, 213-226. doi:10.1002/path.5992. https://pubmed.ncbi.nlm.nih.gov/35894849/

6. Malhotra, Rajeev, Mauer, Andreas C, Lino Cardenas, Christian L, Post, Wendy S, O'Donnell, Christopher J. 2019. HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype. In Nature genetics, 51, 1580-1587. doi:10.1038/s41588-019-0514-8. https://pubmed.ncbi.nlm.nih.gov/31659325/

7. Liu, Fan, Di, Yali, Ma, Wei, Li, Xia, Ji, Zheng. . HDAC9 exacerbates myocardial infarction via inactivating Nrf2 pathways. In The Journal of pharmacy and pharmacology, 74, 565-572. doi:10.1093/jpp/rgab065. https://pubmed.ncbi.nlm.nih.gov/33963859/

8. Dai, Yunjian, Wei, Taofeng, Huang, Yuwen, Lin, Zheng, Dai, Haibin. 2023. Upregulation of HDAC9 in hippocampal neurons mediates depression-like behaviours by inhibiting ANXA2 degradation. In Cellular and molecular life sciences : CMLS, 80, 289. doi:10.1007/s00018-023-04945-y. https://pubmed.ncbi.nlm.nih.gov/37690046/