Table 2.

Roles of HDACs in cardiovascular development and disease

Class	Chromatin Modifying Factor	Cardiovascular Studies in Animals		Comment	Ref
		Tissue of Gene Modification	Phenotype
Class I HDAC	HDAC1	Germline deletion	Lethality before E9.5. General growth retardation.	Hdac1 suppresses Cdk* inhibitor p21 and p27 to promote cell proliferation.	81
		Deletion in myocardium	No apparent cardiac defects.	Hdac1 functions redundantly with Hdac2 in the myocardium.	81
	HDAC2	Germline deletion	Lethality at birth. Thickened myocardium, thickened IVS, hypotrabeculation.	Hdac2-Hop inhibits cardiomyocyte proliferation by suppressing SRF- and Gata4- dependent gene expression.	31, 81
			Surviving adult mice are resistant to hypertrophy.	Hdac2 suppresses Inppf5, which inhibits the pro-hypertrophic Akt/Gsk3β pathway.	31, 93
		Overexpression in myocardium	Cardiac hypertrophy.	Hdac2 overexpression activates the Akt/Gsk3β pathway.	31
		Deletion in myocardium	No apparent cardiac defects.	Hdac2 functions redundantly with Hdac1 in the myocardium.	81
		Deletion of Hdac1 and Hdac2 in myocardium	Lethality within 2 weeks after birth. Arrhythmias, dilated cardiomyopathy.	Hdac1 and Hdac2 interact with REST to repress fetal genes involved in calcium handling and contractility.	81
	HDAC3	Germline deletion	Lethality at E9.5 due to gastrulation defects.	Hdac3 is required for gastrulation.	95
		Overexpression	Cardiac hyperplasia without hypertrophy.	Hdac3 suppresses several Cdk* inhibitors to promote cardiomyocyte proliferation.	94
		Deletion in myocardium	Lethality at 3–4 months after birth. Cardiac hypertrophy, fibrosis, abnormal fatty acid metabolism, lipid accumulation in heart muscle.	Hdac3 suppresses PPARα activity on the promoters of genes involved in metabolic regulation.	95
Class II HDAC	HDAC5 and HDAC9	Germline deletion	Single Hdac5- or Hdac9-null mutation causes no apparent cardiac phenotype. Double Hdac5 and Hdac9 mutations cause lethality starting at E15.5, frequent VSD, and occasional thin myocardium.	Hdac5/9 may suppress the transcriptional activity of Mef2, SRF, or myocardin involved in cardiac growth regulation.	97
			Hdac5- or Hdac9-null mice show enhanced hypertrophic response to cardiac stress, and display protection of female hearts from ischemia injury.	Hdac5/9 suppresses the transcriptional activity of pro-hypertrophic Mef2 and CAMTA2. Hdac5/9 suppresses the Mef2-ERα-Vegfa pathway that promotes angiogenesis in ischemic hearts.	97, 98, 99, 104
	HDAC7	Germline deletion	Lethality at E11.5, severe hemorrhage from leaky and dilated blood vessels.	Hdac7 suppresses Mmp10 in the endothelium to maintain the integrity of vessel wall.	96
Class III HDAC	SIRT1	Germline deletion	Lethality at birth, ASD*, VSD*, heart valve defects.	Sirt1 deacetylates p53, preventing p53 from triggering cell apoptosis after DNA damage and stress.	110, 111, 113
		Overexpression in myocardium	Low/moderate Sirt1 overexpression reduces cardiac hypertrophy and apoptosis. High Sirt1 overexpression triggers cardiac hypertrophy and apoptosis.	Sirt1 expression is activated by cardiac stress, and it regulates the stress response in a dose-dependent manner.	115
	SIRT3	Germline deletion	Cardiac hypertrophy and interstitial fibrosis at 2 months of age.	Sirt3 inhibits apoptosis through activating Ku70-Bax interaction and inhibiting Bax’s pro-apoptotic activity.	118, 120
		Overexpression in myocardium	Resistant to stress-induced cardiac hypertrophy.	Sirt3 activates Foxo3a-dependent antioxidant genes and attenuates the pro-hypertrophic RAS, MAPK/ERK and PI3K/Akt pathways.	120
	SIRT7	Germline deletion	Shortened lifespan, extensive cardiac fibrosis, hypertrophy, and inflammatory cardiomyopathy	Sirt7 deacetylates p53 and protects cardiomyocytes from stress-induced apoptosis.	122

^*Cdk: cycline-depedent kinase. ASD: atrial septal defect. VSD: ventricular septal defect.