Korean Circ J.  2017 May;47(3):392-400. 10.4070/kcj.2016.0266.

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

• Kee HJ
• Kim GR
• Lin MQ
• Choi SY
• Ryu Y
• Jin L
• Piao ZH
• Jeong MH

• KMID: 2385394
• DOI: http://doi.org/10.4070/kcj.2016.0266

Abstract

BACKGROUND AND OBJECTIVES
Dysregulation 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 METHODS
We 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-N(G)-nitro-L-arginine methyl ester (L-NAME) to induce hypertension.
RESULTS
SHR 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.
CONCLUSION
These results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension.

Keyword

Hypertension; Spontaneously hypertensive rats; L-NAME; Angiotensin II; Class II histone deacetylases

MeSH Terms

Angiotensin II
Animals*
Blood Pressure
Histone Deacetylases*
Histones*
Humans
Hypertension
Hypertension, Pulmonary
Mice
Models, Animal*
NG-Nitroarginine Methyl Ester
Rats
Rats, Inbred SHR
Angiotensin II
Histone Deacetylases
Histones
NG-Nitroarginine Methyl Ester

Figure

• 

  Fig. 1 Elevated blood pressures in hypertensive animal models. (A-C) Systolic, diastolic, and mean blood pressures were measured in a conscious state by the tail-cuff method. Twenty-four-week-old SHR and WKY rats were analyzed (n=8 per group). (D-F) After 2 weeks of angiotensin II (Ang II) infusion in mice, blood pressures were determined (n=9 per group). (G-I) Hypertension was induced by treatment with L-NG-nitro-L-arginine methyl ester (0.1% L-NAME, in drinking water) for 2 weeks, after which, the blood pressures were evaluated. **p<0.01 and ***p<0.001 vs. WKY, sham, or control group. SHR: spontaneously hypertensive rats, WKY: Wistar-Kyoto, NS: not significant, L-NAME: L-NG-nitro-L-arginine methyl ester.

• 

  Fig. 2 Class I and IIa/b HDACs expression in spontaneously hypertensive rats. (A) Levels of class I HDACs (HDAC1, 2, 3, and 8) protein expression were determined by western blot analysis using left ventricular tissues from WKY rats and SHR. GAPDH was used as a loading control. (B) Proteins were quantified by densitometry. (C) Levels of cardiac class IIa HDACs (HDAC4, 5, 7, and 9) proteins were assessed in SHR by western blot analysis. (D) Protein levels were quantified by densitometry. (E) Levels of cardiac class IIb HDACs (HDAC6 and HDAC10) proteins were determined by western blot. (F) Quantification of class IIb HDACs. *p<0.05, **p<0.01, and ***p<0.001 vs. WKY. WKY: Wistar-Kyoto, SHR: spontaneously hypertensive rats, HDAC: histone deacetylase, NS: not significant, GAPDH: glyceraldehyde 3-phosphate dehydrogenase.

• 

  Fig. 3 Decreased expression of HDAC8 in angiotensin II-induced hypertensive mice. (A) Levels of class I HDACs (HDAC1, 2, 3, and 8) protein expression were determined by western blot analysis using hearts from angiotensin II (Ang II)-induced hypertensive mice and sham mice. GAPDH was used as a loading control. (B) Proteins were quantified by densitometry. (C) Levels of cardiac class IIa HDACs (HDAC4, 5, 7, and 9) proteins were assessed in Ang II-induced mice by western blot analysis. (D) Protein levels were quantified by densitometry. (E) Levels of cardiac class IIb HDACs (HDAC6 and HDAC10) proteins were determined by western blot. (F) Quantification of class IIb HDACs. ***p<0.001 vs. sham mice. HDAC: histone deacetylase, GAPDH: glyceraldehyde 3-phosphate dehydrogenase.

• 

  Fig. 4 Decreased class IIa HDAC expression in L-NAME-induced hypertensive mice. (A) Levels of class I HDACs (HDAC1, 2, 3, and 8) protein expression were determined by western blot analysis using hearts from L-NAME-induced hypertensive mice and sham mice. GAPDH was used as a loading control. (B) Proteins were quantified by densitometry. (C) Levels of cardiac class IIa HDACs (HDAC4, 5, 7, and 9) proteins were assessed in L-NAME mice by western blot analysis. (D) Protein levels were quantified by densitometry. (E) Levels of cardiac class IIb HDACs (HDAC6 and HDAC10) were determined by western blot. (F) Quantification of class IIb HDACs. *p<0.05 and ***p<0.001 vs. sham mice. L-NAME: L-NG-nitro-L-arginine methyl ester, GAPDH: glyceraldehyde 3-phosphate dehydrogenase.

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