Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Mitral Regurgitation

二尖瓣反流继发偏心心肌细胞肥大的机制

• 批准号: 10565204
• 负责人: Stavros George Drakos
• 金额: $ 59.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565204
• 关键词: Address; Adult; Age; Animals; Cardiac; Cardiac Myocytes; Cell Nucleus; Cell Polarity; Cell Shape; Chronic; Compensation; DNA; DNA Damage; Data; Depressed mood; Development; Dilatation - action; Disease; Echocardiography; Europe; Frequencies; Functional disorder; Genes; Genetic; Genetic Models; Goals; Growth; Heart; Heart Valve Diseases; Heart failure; Human; Hypertrophy; Incidence; Intercalated disc; Iridectomy; Knockout Mice; Left; Left Ventricular Dysfunction; Left Ventricular Remodeling; Length; Link; Mediating; Mediator; Medical; Messenger RNA; Mitral Valve; Mitral Valve Insufficiency; Modeling; Molecular; Morphology; Mus; Myocardial; Myocardial dysfunction; Myocardium; Natural History; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Phase; Polyribosomes; Population; Protein Biosynthesis; Public Health; Publishing; Rattus; Regulation; Research; Role; Secondary to; Shapes; Stimulus; Testing; Thick; Ventricular; ataxia telangiectasia mutated protein; cell growth; directional cell; hemodynamics; mRNA Expression; mRNA Translation; mouse model; novel therapeutic intervention; oxidative DNA damage; postnatal development; pressure; prevent; response; targeted treatment; tool; upstream kinase

Valvular heart disease represents a major public health problem worldwide. The incidence of valvular heart disease increases with age, and it is estimated that about 15% of the population above the age of 75 years suffer from some form of significant valvular disorder. Mitral regurgitation (MR) is the most frequent form of valvular heart diseases, where it is estimated that moderate and severe MR occurs at a frequency of 1.7% as adjusted to the US adult population, and up to 5% of the population in Europe have significant mitral valve disease. The natural history of chronic MR is characterized by a compensated hemodynamic state in its early phases, followed by a gradual progressive left ventricular (LV) remodeling and eccentric hypertrophy resulting in heart failure. MR patients with depressed systolic function can present a difficult management dilemma; corrective valve surgery is not recommended, and medical therapy is ineffective in preventing LV dysfunction. It should perhaps be not surprising that medical therapy for MR has repeatedly failed, since very little is known about the molecular mechanisms of myocardial dysfunction associated with primary severe MR, perhaps owing to the paucity of research tools. One of the major limitations in understanding the molecular mechanisms of myocardial response to severe MR lies in the lack of mouse models. Although several elegant large animal studies, and even a rat MR model have been published, the mechanism of eccentric hypertrophy and myocardial dysfunction secondary to severe MR is not known. Therefore, the overall goal of this project is to understand the mechanistic basis of LV systolic dysfunction secondary to severe MR that can guide the development of new therapeutic strategies. In the current proposal, we developed the first mouse model of MR. Valvular damage was achieved by severing the MV leaflets and chords using iridectomy scissors, and severe MR was confirmed by echocardiography. We found that this model recapitulates the effect of severe MR on the human myocardium with eccentric hypertrophy, systolic dysfunction, and activation of canonical hypertrophy pathways. In addition, we found evidence of activation of directional cell growth as a possible mechanism of longitudinal cardiomyocyte growth in response to MR. Therefore, we hypothesize that MR-induced eccentric cardiomyocyte hypertrophy is mediated by activation of canonical hypertrophy pathways in conjunction with directional cell growth. There are three aims: Determine the role of oxidative DNA damage in regulating eccentric cardiomyocyte hypertrophy in response to severe MR. To determine the role of Crb2 in regulation of cardiomyocyte shape during postnatal development and in response to hypertrophic stimuli. Finally, we aim to identify the spatial pattern of sarcomeric mRNA translation during cardiomyocyte hypertrophy in response to MR.

心脏瓣膜病是世界范围内的一个重大公共卫生问题。心脏瓣膜病的发生率 疾病随着年龄的增长而增加，据估计，75岁以上的人口中约有15% 患有某种形式的严重心脏瓣膜紊乱。二尖瓣返流(MR)是最常见的 心脏瓣膜病，据估计，中度和重度MR发生的频率为1.7% 适应美国成年人口，欧洲高达5%的人口有明显的二尖瓣 疾病。慢性MR的自然病程以早期代偿血流动力学状态为特征。 各阶段，随后逐渐进行的左心室(LV)重构和离心性肥厚导致 在心力衰竭方面。收缩功能受抑的MR患者可能会出现困难的管理困境； 不推荐进行瓣膜矫正术，药物治疗对预防左心功能不全无效。 MR的药物治疗一再失败也许并不令人惊讶，因为人们对此知之甚少。 关于与原发性重症MR相关的心肌功能障碍的分子机制，也许 由于研究工具的缺乏。 了解心肌对严重MR反应的分子机制的主要限制之一 在于缺乏老鼠模型。尽管几项优雅的大型动物研究，甚至是大鼠MR模型 已有文献报道，继发性离心性肥厚和心肌功能不全的机制 严重的MR尚不清楚。因此，本课题的总体目标是了解LV的力学基础。 继发于重度MR的收缩功能障碍，可以指导新的治疗策略的发展。在……里面 目前的建议是，我们研制出第一只小鼠的瓣膜损伤模型是通过切断 经超声心动图证实，用虹膜切除剪刀剪出MV小叶和弦线，并显示重度MR。我们 结果发现，该模型重现了严重MR对偏心性心肌的影响 肥厚、收缩功能障碍和典型肥厚通路的激活。另外，我们发现， 定向细胞生长激活作为心肌细胞纵向生长的可能机制的证据 因此，为了回应MR先生，我们假设MR诱导的离心性心肌细胞肥大是 通过激活规范的肥大通路与定向细胞生长相结合。确实有 三个目标：确定氧化DNA损伤在调节心肌细胞离心性肥大中的作用 对重度MR的反应以确定Crb2在出生后心肌细胞形状调节中的作用 发展和对肥大刺激的反应。最后，我们的目标是确定 心肌细胞肥大过程中肌瘤基因的翻译