Histone Deacetylase Inhibition: A Novel Approach to Cardioprotection

组蛋白脱乙酰酶抑制：心脏保护的新方法

• 批准号: 9704022
• 负责人: TING C ZHao
• 金额: $ 40.96万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9704022
• 关键词: Ablation; Acetylation; Angiogenesis Inhibition; Animal Model; Attenuated; Biological; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Survival; Coronary; Development; Exposure to; Family suidae; Functional disorder; Funding; Future; Genetic; Goals; Grant; HDAC4 gene; Health; Heart; Heart Diseases; Heart Injuries; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Hypoxia; Impairment; In Vitro; Injury; Investigation; Knockout Mice; Lead; Mediating; Modeling; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Pathway interactions; Phosphotransferases; Physiological; Proteasome Inhibition; Protein Isoforms; Proteins; Regulation; Role; Seminal; Signal Transduction; Specificity; Testing; Therapeutic; Time; Ubiquitination; United States; Virus Diseases; angiogenesis; cardiac angiogenesis; cardiac repair; cardioprotection; clinically relevant; design; frontier; functional improvement; heart damage; improved; in vivo; mouse model; multicatalytic endopeptidase complex; myocardial damage; myocardial injury; neovascularization; novel; novel strategies; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; pre-clinical; protective effect; protein degradation; response

Project Summary: Histone deacetylases (HDACs) have emerged as an important mechanism in regulating cardiovascular diseases, and this holds promise in developing efficacious and clinical relevant therapeutic strategies. This is a competitive renewal application to continue our studies of HDAC inhibition, which is critical to the development of myocardial protection. During the past funding periods, we have well established that inhibition of HDAC leads to a profound cardioprotection in attenuating myocardial I/R injury and reversing cardiac remodeling. We have discovered that p38 is subject to regulation by acetylation, and p38 acetylation is associated with HDAC inhibition-induced cardioprotective effects. We have demonstrated that HDAC inhibition enhances cardiac repair through stimulating endogenous myoangiogenesis. Non-specific HDAC inhibition is conceived as a major hurdle to achieving a promising therapeutic implication in the future. Our recent studies have sought to explore the significance of HDAC isoforms in modulating cardiac pathophysiology. Our interesting observation indicated that HDAC 4 isoform mainly involves HDAC inhibitors-induced cellular protection, which was associated with the degradation of HDAC4 protein. p38-regulated/activated kinase (PRAK), an identified novel and poorly characterized p38 substrate, is crucial to enhancing angiogenesis. Our latest discovery indicates that genetic inhibition of PRAK eliminated HDAC inhibition-induced cardioprotection and mitigated angiogenesis. These findings have led us to speculate that inhibition of HDAC4 and subsequent PRAK activation occurs following HDAC inhibition, leading to protective effects. The proposed studies will test the central hypothesis that HDAC4 inhibition-mediated PRAK activation induces myocardial protection and angiogenesis. The specific aims of our proposed studies are the following: Specific Aim 1: Determine the role of HDAC4 and its ubiquitination in mediating myocyte survival in hypoxia in vitro. Specific Aim 2: Determine the in vivo role of cardiac-specific HDAC4 and HDAC inhibitor in myocardial ischemia and angiogenesis. Specific Aim 3: Elucidate HDAC4 deletion or HDAC inhibitor-mediated protection and angiogenesis via PRAK signaling. Specific Aim 4: Define preclinical perspectives of HDAC inhibitor-mediated protection is proteasome pathway using a preclinical large animal model. Taken together, the proposed studies of this competitive renewal application will for the first time establish that HDAC4 associated with PRAK constitutes a crucial pathway to mediate myocardial injury and angiogenesis. All of these studies will not only uncover a novel and exciting mechanism in cell signaling and myocardial protection, but will provide the translational evidence that will have great potential to develop a new therapeutic approach to improve human health.

组蛋白脱乙酰酶(HDAC)已成为调节 心血管疾病，这为开发有效和临床相关的治疗方法带来了希望 战略。这是一个竞争性更新应用，以继续我们对HDAC抑制的研究，这是至关重要的 以促进心肌保护的发展。在过去的资助期，我们已经很好地确立了 抑制HDAC在减轻心肌I/R损伤和逆转心肌损伤中的作用 心脏重塑。我们发现p38受到乙酰化的调节，p38的乙酰化是 与HDAC抑制诱导的心脏保护作用有关。我们已经证明了HDAC抑制 通过刺激内源性肌肉血管生成增强心脏修复。非特异性的HDAC抑制是 被认为是在未来实现有前景的治疗意义的主要障碍。我们最近的研究 试图探讨HDAC异构体在心脏病理生理调控中的意义。我们的 有趣的观察表明，HDAC 4亚型主要涉及HDAC抑制剂诱导的细胞 保护作用与HDAC4蛋白的降解有关。P38-调节/激活的蛋白激酶 (PRAK)是一种被发现的新的、特征不佳的p38底物，对促进血管生成至关重要。我们的 最新发现表明，PRAK的基因抑制消除了HDAC抑制诱导的心脏保护 并抑制血管生成。这些发现使我们推测，HDAC4和随后的抑制 在HDAC被抑制后，PRAK被激活，从而产生保护作用。拟议中的研究将检验 HDAC4抑制介导的PRAK激活诱导心肌保护的中心假说 和血管生成。我们建议的研究的具体目标如下：具体目标1：确定 HDAC4及其泛素化在介导体外缺氧心肌细胞存活中的作用。具体目标2： 确定心脏特异的HDAC4和HDAC抑制物在心肌缺血和再灌注中的作用 血管生成。具体目标3：阐明HDAC4缺失或HDAC抑制剂介导的保护和 通过PRAK信号转导的血管生成。具体目标4：确定HDAC抑制剂介导的临床前前景 保护是使用临床前大型动物模型的蛋白酶体途径。总而言之，拟议的研究 将首次确定HDAC4与PRAK相关联 构成了介导心肌损伤和血管生成的重要途径。所有这些研究不仅将 揭示了细胞信号和心肌保护中一种新的和令人兴奋的机制，但将提供 翻译证据将具有巨大的潜力开发一种新的治疗方法来改善人类 健康。

项目成果

Glucagon-like peptide-1 (GLP-1) and protective effects in cardiovascular disease: a new therapeutic approach for myocardial protection.

• DOI: 10.1186/1475-2840-12-90
• 发表时间: 2013-06-18
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3
• 作者: Zhao TC

Irisin Improves Differentiation through Preserved Mitochondrial Function in Mouse C2C12 Skeletal Muscle Cells.

鸢尾素通过保留小鼠 C2C12 骨骼肌细胞的线粒体功能来促进分化。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Slate-Romano,JohnJ;Yano,Naohiro;Kulthinee,Supaporn;Wang,Lijiang;Zhang,LingZhang;Zhao,Ting
• 通讯作者: Zhao,Ting

Sodium Butyrate Protects -Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice.

• DOI: 10.1002/jcb.25902
• 发表时间: 2017-08
• 期刊: Journal of cellular biochemistry
• 影响因子: 4
• 作者: Zhang L;Du J;Yano N;Wang H;Zhao YT;Dubielecka PM;Zhuang S;Chin YE;Qin G;Zhao TC
• 通讯作者: Zhao TC

Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.

• DOI: 10.1186/s12933-015-0262-8
• 发表时间: 2015-08-07
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3
• 作者: Chen Y;Du J;Zhao YT;Zhang L;Lv G;Zhuang S;Qin G;Zhao TC
• 通讯作者: Zhao TC

Irisin reduces inflammatory signaling pathways in inflammation-mediated metabolic syndrome.

• DOI: 10.1016/j.mce.2022.111676
• 发表时间: 2022-07-15
• 期刊: MOLECULAR AND CELLULAR ENDOCRINOLOGY
• 影响因子: 4.1
• 作者: Slate-Romano, John J.;Yano, Naohiro;Zhao, Ting C.
• 通讯作者: Zhao, Ting C.