Role of dual-specificity phosphatase 5 (DUSP5) in the regulation of right ventric

描述（由申请人提供）：心力衰竭是美国和世界范围内疾病和死亡的主要原因。本病的特征是心脏增大（肥大）和心脏僵硬（纤维化），导致心脏收缩和舒张受损。首次心力衰竭入院后的5年死亡率为40%，强调需要新的治疗策略。组蛋白去乙酰化酶（HDAC）抑制剂已成为一类新的药物，在临床前模型中已被证明可以有效地减少心脏肥厚并最终改善心力衰竭。我们之前发表了HDAC抑制通过上调心肌细胞的核ERK1/2磷酸酶，双特异性磷酸酶5 （DUSP5）来阻断核ERK1/2信号传导，从而导致心肌肥大。然而，DUSP5在心脏中的体内功能尚不清楚。最近的研究表明，核ERK1/2信号是心衰动物模型中病理性心肌肥厚的中枢调节因子。在初步研究中，我们假设DUSP5缺失小鼠由于核ERK磷酸化增强，在应激反应中会出现过度的心脏肥厚。事实上，与使用肾上腺素能激动剂异丙肾上腺素（ISO）治疗的野生型小鼠相比，dusp5缺陷小鼠的左心室（lv）明显增大，ERK1/2激活也增强。奇怪的是，ISO在野生型小鼠中没有诱导RV肥大，但在DUSP5缺失小鼠中却导致RV质量增加约40%。这些数据表明DUSP5在右心室肥大的控制中起着重要作用。值得注意的是，相对于左室肥大，我们对控制病理性右室生长的分子机制知之甚少。这一应用将填补一个关键的空白，通过验证DUSP5通过使核ERK1/2去磷酸化而作为信号依赖的心脏肥厚抑制因子的假设，并且该机制对抑制右心室肥厚尤其重要。为了验证我们的假设，我们制定了两个具体目标。目的1将阐明hdac通过染色质免疫沉淀（ChIP）和DNA甲基化技术控制心肌细胞DUSP5表达的机制，以确定DUSP5启动子内的表观遗传调控事件。在Aim 2中，我们将探讨dusp5在心衰动物模型中控制核ERK1/2磷酸化和病理性RV肥大中的体内作用。拟议的研究将显著增加我们关于右心室生长的有限知识，可能促进开发更好的右侧心力衰竭患者治疗方法。

DESCRIPTION (provided by applicant): Heart failure is a major cause of disease and death in the US and worldwide. Features of this disease are heart enlargement (hypertrophy) and heart stiffness (fibrosis), which result in impaired heart contraction and relaxation. The five-year deat rate following first admission of heart failure is >40%, stressing the need for new therapeutic strategies. Histone deacetylase (HDAC) inhibitors have emerged as a new class of drugs that have been shown as effective in reducing cardiac hypertrophy and ultimately improving heart failure in pre- clinical models. We previously published that HDAC inhibition blocks nuclear ERK1/2 signaling, and thus hypertrophy, by upregulating the nuclear ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5) in cardiac myocytes. However, nothing is known about the in vivo function of DUSP5 in the heart. Recent studies demonstrate that nuclear ERK1/2 signaling is a central regulator of pathological cardiac hypertrophy in animal models of HF. In preliminary studies, we postulated that DUSP5 null mice would develop exaggerated cardiac hypertrophy in response to stress due to enhanced nuclear ERK phosphorylation. Indeed, DUSP5-deficient mice had significantly larger left ventricles (LVs), as well as enhanced ERK1/2 activation, compared to wild- type littermates in response to treatment with the ¿-adrenergic agonist, isoproterenol (ISO). Curiously, ISO did not induce RV hypertrophy in wild-type mice, but triggered a ~40% increase in RV mass in DUSP5 null mice. These data suggest a prominent role for DUSP5 in the control of RV hypertrophy. Significantly, relative to LV hypertrophy, little is known about the molecular mechanisms controlling pathological RV growth. This application will fill a critical void by testing the hypothesis that DUSP5 functions as a signl-dependent repressor of cardiac hypertrophy by dephosphorylating nuclear ERK1/2, and this mechanism is especially critical for suppression of RV hypertrophy. To test our hypothesis, we have developed two specific aims. Aim 1 will elucidate the mechanism(s) by which HDACs control DUSP5 expression in cardiac myocytes using chromatin immunoprecipitation (ChIP) and DNA methylation techniques to determine epigenetic regulatory events within the dusp5 promoter. In Aim 2, we will address the in vivo role ofDUSP5 in the control of nuclear ERK1/2 phosphorylation and pathological RV hypertrophy in animal models of heart failure. The proposed study will significantly add to our limited knowledge regarding RV growth, potentially facilitating development of better therapies for patients with right-sided heart failure.