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, playing a significant role in the human physiological system [4]. It is involved in multiple pathways related to various diseases such as inflammation, cholesterol efflux, and endothelial-mesenchymal transition [1].

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 HDAC9 inhibition could be a novel treatment approach [1]. In male mice, tubule-specific deletion of HDAC9 or its pharmacological inhibition attenuates epithelial cell cycle arrest in G2/M, reducing kidney fibrosis [2]. HDAC9KO mice spontaneously develop age-related intervertebral disc degeneration (IVDD), and overexpression of HDAC9 in nucleus pulposus (NP) cells alleviates IVDD symptoms in a mouse model, indicating its role in IVDD [3]. In matrix Gla protein-deficient mice (a model of human vascular calcification), mice lacking HDAC9 have reduced aortic calcification and improved survival [5]. Also, HDAC9 knockout protects the heart from myocardial infarction injury by activating the Nrf2 pathway [6].

In conclusion, HDAC9 is involved in multiple biological processes and disease conditions. Gene knockout mouse models have been crucial in revealing its role in atherosclerotic disease, kidney fibrosis, IVDD, vascular calcification, and myocardial infarction, providing potential therapeutic targets for these diseases.

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. 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/

6. 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/