The methyltransferase Smyd1 regulates cardiac physiology

甲基转移酶 Smyd1 调节心脏生理学

• 批准号: 10522980
• 负责人: Sarah Franklin
• 金额: $ 40.04万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522980
• 关键词: Adult; Arteries; Binding; Blood flow; Cardiac; Cardiac Myocytes; Cause of Death; Cells; ChIP-seq; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Congestive Heart Failure; Coronary Arteriosclerosis; Crista ampullaris; Data; Disease; Down-Regulation; Electron Microscopy; Electron Transport; Epigenetic Process; Event; Exhibits; Fluorometry; Gene Expression; Genes; Genetic Transcription; Health; Heart failure; Histone Deacetylase; Histone-Lysine N-Methyltransferase; Histones; Human; Hypertrophic Cardiomyopathy; Ischemia; Knockout Mice; Mediating; Metabolism; Methylation; Methyltransferase; Mitochondria; Molecular; Morphology; Mus; Muscle Cells; Mutation; Myocardial Ischemia; Myocardial dysfunction; Myocardium; OPA1 gene; Orthologous Gene; Pathogenicity; Pathologic; Pathway interactions; Patients; Physiology; Prevention therapy; Production; Protein Isoforms; Protons; Publishing; Regulation; Reperfusion Therapy; Resolution; Respiration; Respiratory Chain; Role; Structure; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcript; Transgenic Mice; Variant; effective therapy; gain of function; genome-wide; heart metabolism; human disease; human tissue; in vivo; induced pluripotent stem cell; insight; ischemic injury; loss of function; mouse model; myocardial injury; novel; overexpression; prevent; promoter; protein expression; therapeutic target

PROJECT SUMMARY Coronary artery disease is the leading cause of death in the US and is the primary cause of chronic heart failure. For patients with coronary artery disease, some advancements have been made clinically to restore blood flow in diseased arteries and reduce myocardial injury from the resulting ischemia and subsequent reperfusion. However, even with these advancements one quarter of patients will die or develop heart failure within 1 year. Damage to the myocardium during ischemic injury includes deficiencies in metabolism and energetics. Some key epigenetic regulators can prevent or reduce ischemic injury and pathological remodeling in murine models, however, their ubiquitous expression has made them unsuitable for therapeutic targeting in humans, thus far. In contrast, we recently identified the only known myocyte-specific epigenetic regulator of mitochondrial energetics and metabolism – the histone lysine methyltransferase Smyd1 – which holds great therapeutic potential given its tissue-specific expression. Specifically, we performed the first analysis of Smyd1 function in the adult myocardium using inducible, cardiomyocyte-specific Smyd1 knockout mice and showed that loss of Smyd1 leads to dysregulated cardiac metabolism and suppressed mitochondrial respiration, ultimately leading to heart failure (published in AJP). Subsequently we showed that down-regulation of mitochondrial energetics is an early event in these knockout mice (occurring before the onset of cardiac dysfunction) and results, at least in part, from Smyd1’s regulation of PGC-1α transcription (published in PNAS). To further understand Smyd1’s role in regulating cardiac physiology we recently generated transgenic mice allowing inducible, cardiomyocyte-specific overexpression of the Smyd1a isoform (the mouse ortholog to human SMYD1) and subjected these mice to permanent occlusion of the LAD. Our unpublished preliminary results show that Smyd1a gain-of-function can enhance mitochondrial respiration and protect from ischemic injury, although how this is accomplished molecularly is unknown. In addition, our preliminary data from these mice show increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae, concomitant with increased Opa1 expression, a known driver of cristae morphology. These results implicate Opa1 as a novel, functionally important downstream target of Smyd1a whereby cardiomyocytes upregulate energy efficiency, protecting them from ischemic injury. Our overarching hypothesis is that Smyd1a protects from ischemic injury by regulating mitochondrial energetics and enhancing respiration efficiency in the cardiomyocyte through regulation of both: 1) PGC-1α expression (a regulator of electron transport chain gene expression) and 2) OPA1-mediated cristae remodeling and stabilization of electron transport chain supercomplexes. We will test this hypothesis in our transgenic mice which conditionally overexpress Smyd1a. In addition, we will examine these pathways in cells and human tissue with a putative SMYD1 loss-of-function variant, N101S, which we identified with collaborators at the U. of Pittsburgh (Dr Lina Gonzalez) in a patient with hypertrophic cardiomyopathy and heart failure.

项目摘要 冠状动脉疾病是美国死亡的主要原因，也是慢性心力衰竭的主要原因。 对于冠状动脉疾病患者，临床上已经取得了一些进展，以恢复血流 在患病的动脉和减少心肌损伤所造成的缺血和随后的再灌注。 然而，即使有这些进步，四分之一的患者将在1年内死亡或发生心力衰竭。 缺血性损伤时心肌的损伤包括代谢和能量的不足。一些 关键的表观遗传调节剂可以预防或减少鼠模型中的缺血性损伤和病理性重塑， 然而，到目前为止，它们的普遍表达使得它们不适合用于人类的治疗靶向。在 相反，我们最近发现了唯一已知的肌细胞特异性线粒体能量表观遗传调节因子 和代谢-组蛋白赖氨酸甲基转移酶Smyd 1-它具有巨大的治疗潜力， 其组织特异性表达。具体地说，我们在成人中进行了Smyd 1功能的首次分析， 使用可诱导的心肌细胞特异性Smyd 1敲除小鼠的心肌，并显示Smyd 1导致的丢失 心脏代谢失调和线粒体呼吸抑制，最终导致心力衰竭 （发表于AJP）。随后，我们发现线粒体能量的下调是一个早期事件， 在这些基因敲除小鼠中（发生在心功能障碍发作之前），至少部分原因是 Smyd 1对PGC-1α转录的调节（发表于PNAS）。为了进一步了解Smyd 1在 调节心脏生理学，我们最近产生了转基因小鼠，允许诱导，心肌细胞特异性 Smyd 1a同种型（人SMYD 1的小鼠直系同源物）的过表达，并使这些小鼠 永久性封堵LAD。我们未发表的初步结果表明，Smyd 1a功能增益可以 增强线粒体呼吸和保护免受缺血性损伤，尽管这是如何实现的， 分子上是未知的。此外，我们从这些小鼠获得的初步数据显示， 嵴内呼吸链超复合物的形成和稳定，伴随着增加 opa 1表达，一种已知的嵴形态驱动因素。这些结果暗示Opa 1是一种新的，功能上 Smyd 1a的重要下游靶点，使心肌细胞上调能量效率，保护它们 缺血性损伤我们的总体假设是Smyd 1a通过调节 线粒体能量学并通过调节以下两者来增强心肌细胞中的呼吸效率： 1)PGC-1α表达（电子传递链基因表达的调节因子）和2）OPA 1介导的嵴 电子传递链超复合物的重塑和稳定。我们将在我们的 条件性过表达Smyd 1a的转基因小鼠。此外，我们还将研究细胞中的这些通路， 和人类组织中的一个假定的SMYD 1功能丧失变异体，N101 S，我们与合作者确定 在联合匹兹堡（丽娜冈萨雷斯博士）在一个病人与肥厚型心肌病和心力衰竭。