Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models

Abstract

Background and ObjectivesDysregulation of histone deacetylase expression and enzymatic activity is associated with a number of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymatic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models.Subjects and MethodsWe used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to induce hypertension, via osmotic mini-pump for 2 weeks, and (iii) mice that were allowed to drink L-NG-nitro-L-arginine methyl ester (L-NAME) to induce hypertension.ResultsSHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were observed in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addition, a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR.ConclusionThese results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension.

Sodium butyrate attenuates angiotensin II‐induced cardiac hypertrophy by inhibiting COX2/PGE2 pathway via a HDAC5/HDAC6‐dependent mechanism

“…37 For example, cardiac HDAC2 is activated in the heart in response to pressure overload due to aortic constriction 29 ; HDAC4 is increased in the heart of HFD-fed or STZ-induced diabetic mice 26,38 ; HDAC6 and 8 are up-regulated in the heart of DOCA/salt hypertensive rat 39 ; the protein levels of HDAC4, 5, 7, 6 and 10 are increased in spontaneous hypertension rats (SHRs) compared with Wistar Kyoto rats. 40 It is interesting to note that our results about the role of HDAC5 are opposite to that of the previous study that knocking out of HDAC5 enhanced cardiac hypertrophy in a pressure over-loaded mice model. 37 A more recent study shows that the beneficial effect of NaBu on cardiac hypertrophy is mediated by down-regulation of class I HDACs (specifically HDAC2) without any effect on class II HDACs such as HDAC5, in partial abdominal aortic constriction rat model 29 based on the mRNA expression changes in HDACs after NaBu treatment.…”

“…It should be noted that the present study does not provide an explanation for the reason why HDAC5 may have an opposing role to the other class I or II HDACs in cardiac hypertrophy . For example, cardiac HDAC2 is activated in the heart in response to pressure overload due to aortic constriction; HDAC4 is increased in the heart of HFD‐fed or STZ‐induced diabetic mice; HDAC6 and 8 are up‐regulated in the heart of DOCA/salt hypertensive rat; the protein levels of HDAC4, 5, 7, 6 and 10 are increased in spontaneous hypertension rats (SHRs) compared with Wistar Kyoto rats . It is interesting to note that our results about the role of HDAC5 are opposite to that of the previous study that knocking out of HDAC5 enhanced cardiac hypertrophy in a pressure over‐loaded mice model .…”

Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy

“…Along with HDAC1 and HDAC2 levels, HDAC3 level was also found to be increased in a hypoxia-induced pulmonary hypertensive rat model . Moreover, HDAC3 expression was found to be induced in spontaneously hypertensive rats (SHRs) . Nozik-Grayck and co-workers showed that histone deacetylation through HDAC3 reduced the expression of extracellular superoxide dismutase (SOD) in pulmonary artery smooth muscle cells (PASMCs), and HDAC3 inhibitors help to protect against idiopathic pulmonary arterial hypertension (IPAH) by enhancing the level of PASMC SOD3 expression.…”

“…237 Moreover, HDAC3 expression was found to be induced in spontaneously hypertensive rats (SHRs). 238 Nozik-Grayck and co-workers 152 showed that histone deacetylation through HDAC3 reduced the expression of extracellular superoxide dismutase (SOD) in pulmonary artery smooth muscle cells (PASMCs), and HDAC3 inhibitors help to protect against idiopathic pulmonary arterial hypertension (IPAH) by enhancing the level of PASMC SOD3 expression. HDAC3 was also found to be overexpressed in an experimental model of heart failure.…”

Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertension

“…Although cardiac HDAC6 activity was shown to be increased in chronic hypertension [27], the HDAC6-selective inhibitor tubastatin A did not reduce hypertension in Ang II-infused mice [28]. Recently, we reported that the protein levels of class IIa/b HDACs (HDAC4,5,7, 6, and 10) are induced in SHR hearts [29] but not in Ang II mouse hearts. Currently, the HDAC isoform that likely plays a key role in the regulation of hypertension remains unclear.…”