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：
10666617
负责人：
Sarah Franklin
金额：
$ 38.8万
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/10666617
关键词：
Adult Arteries Binding Blood flow Cardiac Cardiac Myocytes Cause of Death Cell Separation 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 Spirometry Structure Tertiary Protein Structure Testing Therapeutic Therapeutic Intervention Tissues Transcript Transgenic Mice Variant Ventricular effective therapy energy efficiency 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。对于冠状动脉疾病的患者，在临床上已取得一些进步以恢复血液流量在解散的动脉中减少了产生的血压和亚脱渗液的心肌损伤。但是，即使有这些进步，有四分之一的患者也会在1年内死亡或发展心力衰竭。缺血性损伤期间心肌的损害包括新陈代谢和能量的缺陷。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重塑，但是，到目前为止，它们的无处不在表达使他们不适合对人类的治疗靶向对比，我们最近确定了线粒体能量的已知的心肌细胞特异性表观调节剂和代谢 - 组蛋白赖氨酸甲基甲基转移酶Smyd1-具有巨大的治疗潜力它的组织特异性表达。使用诱导的，心肌细胞特异性SMYD1敲除小鼠的心肌，并显示出Smyd1铅的损失为了失调的心脏代谢和抑制Mitchondrial呼吸，最终导致心力衰竭（在AJP中出版）。在这些敲除小鼠中（发生在心脏功能障碍发作之前），至少部分是从 SMYD1对PGC-1α转录的调节（在PNA中发表）。调节心脏生理学我们的配方会产生的转基因小鼠允许诱导，心肌细胞特异性小鼠 Smyd1a同工型（小鼠与人类Smyd1的直系同源物）的过表达，并将小鼠进行我们未发表的初步结果的永久性阻塞表明，增强线粒体呼吸并防止缺血性损伤，Althooth如何实现这一目标除了分子是未知的。 Cristae内呼吸链超复合物的形成和稳定，随之增加 OPA1表达，这些结果的已知驱动力。 Important DownStream Target of Smyd1a WheryByByByByByByByByByByBYBYBYBYBYBYBYBYBYBYBYBYBYBYBY BY BY BY BY BY BYGULATE ENERGY E someshot, PROTECTING THEM 由于缺血性损伤。线粒体的能量学和通过调节双重性心肌的呼吸效率提高： 1）PGC-1α表达（电子传输链基因表达的常规者）和2）OPA1介导的Cristae 电子传输链超复合物的重塑和稳定。转基因小鼠过表达SMYD1A。和具有推定的SMYD1功能丧失变体N101S的人体组织，我们与合作者一起确定在匹兹堡大学（Lina Gonzalez博士），患有肥厚性心肌病和头部心力衰竭的患者。