p38 acetylation: Novel signaling mechanisms and myocardial protection

描述（由申请人提供）：缺血性心脏病是当今世界患者死亡的主要原因。在缺血过程中发现新的机制和发展有效的和临床相关的治疗策略有望在缺血性心脏的治疗。最新的证据表明，在介导心肌缺血损伤的主要机制途径是乙酰化/去乙酰化。我们最近的重点工作表明，抑制组蛋白去乙酰化酶（HDAC）导致深刻的心脏保护，这与p38丝裂原活化蛋白激酶密切相关。P38是调控心肌缺血损伤、发育和肥厚反应的重要机制之一。通过使用跨学科的方法，我们的创新发现最近证明p38受乙酰化调节。我们已经确定p38分别在赖氨酸15、53和121个氨基酸残基处乙酰化。有趣的初步研究和我们实验室的既定工作强烈支持p38乙酰化在保护心脏免受缺血性损伤中的功能作用。然而，p38乙酰化介导心脏损伤和保护的生理功能和分子机制尚不清楚。这些令人兴奋的新发现支持了我们目前的假设，即p38乙酰化是心肌保护和调节下游底物HDAC4的关键信号机制，在保护事件的发生中形成伙伴关系。我们提出的研究的具体目的如下：具体目的1：确定p38乙酰化是否对心肌细胞在体外缺氧条件下存活至关重要。目的2：阐明p38乙酰化在心肌损伤和心脏重构中的生理作用。特异性目的3：研究p38乙酰化介导的HDAC4失活在心脏保护调节中的作用。特异性目的4：利用临床前大型动物模型研究p38乙酰化在HDAC抑制诱导的心肌保护中的作用。综上所述，提出的目标将首次确定与HDAC4失活相关的p38乙酰化激活可预防心肌损伤。所有这些研究不仅将揭示细胞信号传导和心肌保护的一个新的和令人兴奋的机制，而且将有很大的潜力开发一种新的治疗方法来改善人类健康。

DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of deaths among patients in the world today. Discovering novel mechanisms during ischemia and developing efficacious and clinically relevant therapeutic strategies hold promise in the treatment of the ischemic heart. The latest emerging evidence suggests that among the leading mechanistic approaches in mediating myocardial ischemic injury is acetylation/deacetylation. Our recent focused works have demonstrated that inhibition of histone deacetylases (HDAC) leads to a profound cardioprotection, which is closely associated with p38 mitogen-activated protein kinase. p38 is one of the most important mechanisms in regulation of myocardial ischemic injury, development, and hypertrophic response. By using interdisciplinary approaches, our innovative discovery recently documented that p38 is subject to regulation by acetylation. We have identified that p38 is acetylated at lysines 15, 53, and 121 amino residues, respectively. The intriguing preliminary study and established works from our lab strongly support a functional role for p38 acetylation in protecting the heart against ischemic injury. However, the physiological function and molecular mechanism by which acetylation of p38 mediates cardiac injury and protection remain unknown. These exciting and novel findings lead to our current hypothesis that p38 acetylation is a signaling mechanism critical for myocardial protection and regulation of downstream substrate HDAC4 to form a partnership in the genesis of protective events. The specific aims of our proposed studies are the following: Specific Aim 1: Determine if p38 acetylation is essential for cardiomyocytes to survive against hypoxia in vitro. Specific Aim 2: Elucidate the physiological role of p38 acetylation in mediating myocardial injury and cardiac remodeling. Specific Aim 3: Investigate the role of p38 acetylation-mediated HDAC4 inactivation in the regulation of cardioprotection. Specific Aim 4: Use a preclinical large animal model to examine the role of p38 acetylation in HDAC inhibition-induced myocardial protection. Taken together, the proposed aims will for the first time establish that activation of p38 acetylation associated with HDAC4 inactivation prevents myocardial injury. All of these studies will not only uncover a novel and exciting mechanism in cell signaling and myocardial protection, but will also have great potential to develop a new therapeutic approach to improve human health.