The methyltransferase Smyd1 regulates cardiac physiology

甲基转移酶 Smyd1 调节心脏生理学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要冠状动脉疾病是美国的首要死因，也是慢性心力衰竭的主要原因。对于冠状动脉疾病患者，临床上已取得一些进展以恢复血流并减少因缺血和随后的再灌注引起的心肌损伤。然而，即使有了这些进步，四分之一的患者仍将在一年内死亡或出现心力衰竭。缺血性损伤期间的心肌损伤包括新陈代谢和能量学方面的缺陷。关键的表观遗传调节因子可以预防或减少小鼠模型中的缺血性损伤和病理重塑，然而，迄今为止，它们的普遍表达使得它们不适合用于人类的治疗靶向。相比之下，我们最近发现了唯一已知的线粒体能量学的心肌细胞特异性表观遗传调节因子和代谢——组蛋白赖氨酸甲基转移酶 Smyd1——具有巨大的治疗潜力具体来说，我们对成人中的 Smyd1 功能进行了首次分析。使用可诱导的、心肌细胞特异性 Smyd1 敲除小鼠对心肌进行研究，结果表明 Smyd1 的缺失会导致导致心脏代谢失调并抑制线粒体呼吸，最终导致心力衰竭（发表于 AJP）随后我们证明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生之前），并且至少部分是由 Smyd1 对 PGC-1α 转录的调控（发表于 PNAS）进一步了解 Smyd1 在 PGC-1α 转录中的作用。调节心脏生理学我们最近培育了转基因小鼠，允许诱导，心肌细胞特异性 Smyd1a 亚型（人类 SMYD1 的小鼠直系同源物）的过度表达并使这些小鼠接受我们未发表的初步结果表明，Smyd1a 可以实现 LAD 的永久闭塞。增强线粒体呼吸并防止缺血性损伤，尽管这是如何实现的此外，我们对这些小鼠的初步数据显示线粒体嵴增加。嵴内呼吸链超复合物的形成和稳定，伴随着增加 Opa1 表达是嵴形态的已知驱动因素，这些结果表明 Opa1 是一种新型的、功能性的。 Smyd1a 的重要下游靶标，心肌细胞借此上调能量效率，保护它们我们的首要假设是 Smyd1a 通过调节来防止缺血性损伤。线粒体能量学并通过调节以下两者来提高心肌细胞的呼吸效率： 1) PGC-1α 表达（电子传递链基因表达的调节因子）和 2) OPA1 介导的嵴我们将在我们的研究中测试这个假设。条件性过度表达 Smyd1a 的转基因小鼠此外，我们将检查细胞中的这些途径。以及我们与合作者共同鉴定出具有推定 SMYD1 功能丧失变体 N101S 的人体组织匹兹堡大学（Lina Gonzalez 博士）治疗患有肥厚性心肌病和心力衰竭的患者。