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.

瓣膜性心脏病是世界范围内的主要公共卫生问题。心脏瓣膜病的发病率 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% 患有某种严重的瓣膜疾病二尖瓣返流（MR）是最常见的 瓣膜性心脏病，估计中度和重度二尖瓣返流的发生率为1.7%， 根据美国成年人群进行调整，欧洲高达5%的人群具有显著的二尖瓣 疾病慢性二尖瓣返流的自然病程的特征是在其早期存在代偿性血流动力学状态， 阶段，随后是逐渐进行性的左心室（LV）重塑和离心性肥大， 心脏衰竭患有收缩功能低下的MR患者可能会出现难以管理的困境; 不推荐进行矫正瓣膜手术，并且药物治疗在预防LV功能障碍方面无效。 这也许并不奇怪，医学治疗MR一再失败，因为很少有人知道 关于与原发性严重MR相关的心肌功能障碍的分子机制， 由于缺乏研究工具。 理解心肌对严重MR反应的分子机制的主要局限之一是 在于缺乏小鼠模型。虽然几个优雅的大型动物研究，甚至一个大鼠MR模型， 已经发表，离心性肥厚和心肌功能障碍的机制继发于 严重的MR是未知的。因此，本项目的总体目标是了解LV的机制基础 继发于严重MR的收缩功能障碍，可以指导新治疗策略的开发。在 根据目前的建议，我们开发了第一个MR小鼠模型。 二尖瓣瓣叶和腱索使用虹膜切除剪，严重二尖瓣返流证实了超声心动图。我们 发现该模型概括了严重MR对具有偏心性的人类心肌的影响， 肥大、收缩功能障碍和典型肥大途径的激活。此外，我们还发现， 定向细胞生长激活作为心肌细胞纵向生长可能机制的证据 因此，我们假设MR诱导的离心性心肌细胞肥大， 通过与定向细胞生长结合的典型肥大途径的激活来介导。有 三个目的：确定氧化性DNA损伤在调节离心性心肌细胞肥大中的作用， 为了确定Crb 2在出生后心肌细胞形状调节中的作用， 发育和对肥大刺激的反应。最后，我们的目标是确定的空间格局， 心肌细胞肥大对MR反应时肌节mRNA的翻译