Myocardial-specific Hdac3 deletion induces by ventricular remodeling in mice

Yuhang CHEN; Rui HE; Yujun SHI; Li SU

doi:10.16016/j.1000-5404.201712165

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Myocardial-specific Hdac3 deletion induces by ventricular remodeling in mice

Basic Medicine | 更新时间：2026-01-09

- Myocardial-specific Hdac3 deletion induces by ventricular remodeling in mice
- Journal of Third Military Medical University Vol. 40, Issue 13, Pages: 1205-1212(2018)
- 作者机构：
  
  1.400014 重庆，重庆医科大学附属第二医院心血管内科
  2.610041 成都，四川大学华西医院病理研究室
- 作者简介：
- 基金信息：
- DOI：10.16016/j.1000-5404.201712165
  CLC： R322.11;R363.21;R394.3
- Received：19 December 2017，
  
  Revised：2018-02-13，
  
  Published：15 July 2018
- 稿件说明：
移动端阅览
Yuhang CHEN, Rui HE, Yujun SHI, et al. Myocardial-specific Hdac3 deletion induces by ventricular remodeling in mice[J]. Journal of Third Military Medical University, 2018, 40(13): 1205-1212.
DOI：

Yuhang CHEN, Rui HE, Yujun SHI, et al. Myocardial-specific Hdac3 deletion induces by ventricular remodeling in mice[J]. Journal of Third Military Medical University, 2018, 40(13): 1205-1212. DOI： 10.16016/j.1000-5404.201712165.

摘要

目的

观察在他莫昔芬诱导下，心肌特异性Hdac3基因缺失对小鼠心脏病理结构及其心脏功能的影响。

方法

利用Cre/Loxp基因重组系统，将Hdac3

loxp/loxp

小鼠与Myh6-creERT小鼠进行杂交，获得带有心肌特异性启动子的Myh6-creERT/Hdac3

loxp/loxp

小鼠，并按随机数字表法将28只8周龄雄性Myh6-creERT/Hdac3

loxp/loxp

小鼠分为对照组、模型组。模型组小鼠腹腔注射0.2 mL他莫昔芬(40 mg/mL)，每天1次，连续5 d，从而诱导性敲除心肌特异性Hdac3基因；对照组小鼠注射0.2 mL的玉米油。在模型建立后第1、4周，采用经胸二维超声心动图检测两组小鼠舒张末期室间隔厚度(diastolic interventricular septum，IVSd)、舒张末期左室后壁厚度(diastolic left ventricular posterior wall，LVPWd)、射血分数(ejection fraction

EF)、左室短轴缩短率(fractional shortening

FS)。随后获取并观察小鼠心脏组织，采用HE染色、Masson三色染色、天狼星红染色、WGA免疫荧光染色检测小鼠心脏病理改变。采用TUNEL检测心肌细胞凋亡水平，Western blot检测DNA损伤相关指标。

结果

Hdac3基因缺失后，与对照组相比，模型组小鼠IVSd与LVPWd明显增高(

＜0.05)，EF与FS明显降低(

＜0.05)。病理学观察结果显示，与对照组相比，模型组小鼠于Hdac3基因敲除后第1周，心肌细胞排列紊乱，横断面显示心肌细胞肥大，间质纤维化增多，伴有少量的炎症细胞浸润；第4周可见弥漫的心肌纤维化与肥大不规则的心肌细胞。TUNEL免疫荧光染色显示模型组凋亡细胞较对照组显著增多(

＜0.05)；Western blot检测结果显示，模型组γH

AX蛋白表达量显著高于对照组(

＜0.05)。

结论

小鼠心肌特异性Hdac3基因的缺失能够引起DNA损伤并诱导心肌细胞凋亡，导致心肌细胞发生病理性结构改变及心脏功能降低，最终引起心室重构。

Abstract

Objective

To investigate the effect of myocardial-specific Hdac3 knockout on cardiac pathological structure and cardiac function in mice under the inducement of tamoxifen (TAM).

Methods

Through the Cre/Loxp gene recombination system

Hdac3

loxp/loxp

mice were hybridized with Myh6-creERT mice to obtain Myh6-creERT/Hdac3

loxp/loxp

mice. Then the obtained 28 8-week-old male Myh6-creERT/Hdac3

loxp/loxp

mice were randomly divided into control group and model group. The mice in the model group were intraperitoneally injected with 40 mg/(mL·d) TAM for 5 consecutive days to knockout the myocardial-specific Hdac3 gene

while those from the control group were injected with same dose of corn oil. In 1 and 4 weeks after model establishment

2-D transthoracic echocardiography was used to detect end diastolic interventricular septum thickness (IVSd)

end diastolic left ventricular posterior wall thickness (LVPWd)

ejection fraction (EF)

and left ventricular fractional shortening (FS). Then the cardiac tissue of mice were harvested for gross observation and pathological changes by HE staining

Masson trichrome staining

Sirius Red staining and WGA immunofluorescence staining. Terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was employed to measure the cardiomyocyte apoptosis

and Western blotting was adopted to detect DNA damage related indicator.

Results

Compared with the control group

the values of IVSd and LVPWd were increased significantly (

0.05)

while those of EF and FS were decreased markedly (

0.05) in the model group after the deletion of Hdac3 gene in the mouse heart. Pathological study displayed that in 1 week after gene deletion

muscle cells in disordered arrangement

hypertrophic muscle cells in cross-sectional area

and increased interstitial fibrosis with a small amount of inflammatory cell infiltration were observed in the model group mice

whereas diffuse myocardial fibrosis with hypertrophic irreg

ular cardiomyocytes were found in the 4th week. TUNEL showed an increase in apoptotic cells in the model group than the control group (

0.05). Western blotting indicated that the expression of γH

AX was increased in the model group (

0.05).

Conclusion

Mouse myocardial-specific Hdac3 gene deletion induces DNA damage and cardiomyocyte apoptosis

results in pathological changes in cardiac myocytes and decreased cardiac function

and eventually leads to ventricular remodeling.

关键词

Keywords

references

黄峻.中国心力衰竭流行病学特点和防治策略[J].中华心脏与心律电子杂志, 2015, 3(2): 81-82.DOI: 10.3877/cma.j.issn.2095-6568.2015.2.002.

HUANG J. The epidemiological characteristics and control strategy of China heart failure[J]. Chin J Heart&Heart Rhythm Electron, 2015, 3(2): 81-82. DOI: 10.3877/cma.j.issn.2095-6568.2015.2.002.

HEUSCH G, LIBBY P, GERSH B, et al. Cardiovascular remodelling in coronary artery disease and heart failure[J]. Lancet, 2014, 383(9932): 1933-1943. DOI: 10.1016/s0140-6736(14)60107-0.

SCHONES D E, ZHAO K J. Genome-wide approaches to studying chromatin modifications[J]. Nat Rev Genet, 2008, 3(9): 179-191. DOI: 10.1038/nrg2270.

TANG J, YAN H, ZHUANG S. Histone deacetylases as targets for treatment of multiple diseases[J]. Clin Sci, 2013, 124(11): 651-662. DOI: 10.1042/CS20120504.

KANEDA R, UENO S, YAMASHITAY, et al. Genome-wide screening for target regions of histone deacetylases in cardiomyocytes[J]. Circ Res, 2005, 97(3): 210-218. DOI: 10.1161/01.RES.0000176028.18423.07.

MANO H. Epigenetic abnormalities in cardiac hypertrophy and heart failure[J]. Environ Health Prev Med, 2008, 13(1): 25-29. DOI: 10.1007/s12199-007-0007-8.

MCKINSEY T A, OLSON E N. Cardiac histone acetylation-therapeutic opportunities abound[J]. Trends Genet, 2004, 20(4): 206-213. DOI: 10.1016/j.tig.2004.02.002.

MONTGOMERY R L, DAVIS C A, POTTHOFF M J, et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility[J]. Genes Dev, 2007, 21(14): 1790-1802. DOI: 10.1101/gad.1563807.

LEWANDOWSKI S L, JANARDHAN H P, SMEE K M, et al. Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis[J]. Hum Mol Genet, 2014, 23(14): 3801-3809. DOI: 10.1093/hmg/ddu093.

TRIVEDI C M, LUO Y, YIN Z, et al. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity[J]. Nat Med, 2007, 13(3): 324-331. DOI: 10.1038/nm1552.

TRIVEDI C M, LU M M, WANG Q, et al. Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy[J]. J Biol Chem, 2008, 283(39): 26484-26489. DOI: 10.1074/jbc.M803686200.

HABERLAND M, MONTGOMERY R L, OLSON E N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy[J]. Nat Rev Genet, 2009, 10(1): 32-42. DOI: 10.1038/nrg2485.

KEE H J, KOOK H. Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy[J]. J Biomed Biotechnol, 2011, 1:928326. DOI: 10.1155/2011/928326.

CHANG S, MCKINSEY T A, ZHANG C L, et al. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development[J]. Mol Cell Biol, 2004, 24(19): 8467-8476. DOI: 10.1128/MCB.24.19.8467-8476.2004.

[FISCHLE W, DEQUIEDT F, HENDZEL M J, et al. Enzymatic activity associated with class Ⅱ HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR[J ] . Mol Cell, 2002, 9(1): 45-57. DOI: http://dx.doi.org/10.1016/S1097-2765(01)00429-4 http://dx.doi.org/10.1016/S1097-2765(01)00429-4 .

GREGOIRE S, XIAO L, NIE J, et al. Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2[J]. Mol Cell Biol, 2007, 27(4): 1280-1295. DOI: 10.1128/MCB.00882-06.

KIM Y, PHAN D, VAN ROOIJ E, et al. The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice[J]. J Clin Invest, 2008, 118(1): 124-132. DOI: 10.1172/JCI33255.

MONTGOMERY R L, POTTHOFF M J, HABERLAND M, et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice[J]. J Clin Invest, 2008, 118(11): 3588-3597. DOI: 10.1172/JCI35847.

MCMURRAY J J. Clinical practice. Systolic heart failure[J]. N Engl J Med, 2010, 362(3): 228-238. DOI: 10.1056/NEJMcp0909392.

SHAH A M, MANN D L. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science[J]. Lancet, 2011, 378 (9792): 704-712. DOI: 10.1016/s0140-6736(11)60894-5.

ROOS W P, KAINA B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis[J]. Cancer Lett, 2013, 332(2): 237-248. DOI: 10.1016/j.canlet.2012.01.007.

BHASKARA S, KNUTSON S K, JIANG G, et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability[J]. Cancer Cell, 2010, 18(5): 436-447. DOI: 10.1016/j.ccr.2010.10.022.

BHASKARA S, CHYLA B J, AMANN J M, et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control[J]. Mol Cell, 2008, 30(1): 61-72. DOI: 10.1016/j.molcel.2008.02.030.

THIAGARAJAN D, ANANTHAKRISHNAN R, ZHANG J, et al. Aldose Reductase acts as a selective derepressor of PPARgamma and the retinoic acid receptor[J]. Cell Rep, 2016, 15(1): 181-196. DOI: 10.1016/j.celrep.2016.02.086.

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