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; 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.

瓣膜心脏病代表了全球一个主要的公共卫生问题。瓣膜心脏的发病率 疾病随着年龄的增长而增加，据估计，大约15％的人口超过75岁 患有某种形式的明显瓣膜疾病。二尖瓣反流（MR）是最常见的形式 瓣膜心脏疾病，据估计中度和重度MR的发生频率为1.7％ 适应美国成年人口，欧洲多达5％的人口具有明显的二尖瓣 疾病。慢性MR的自然历史的特征是早期的血液动力学状态 阶段，然后进行逐渐进行的左心室（LV）重塑和偏心肥厚 心力衰竭。 MR收缩功能抑郁症患者可能会出现困难的管理困境。 不建议进行矫正瓣膜手术，并且药物治疗在防止LV功能障碍方面无效。 MR的医疗疗法反复失败也许不足为奇，因为鲜为人知 关于与原发性严重MR相关的心肌功能障碍的分子机制，也许 由于缺乏研究工具。 了解心肌反应对严重MR的分子机制的主要局限性之一 在于缺乏小鼠模型。虽然几项优雅的大型动物研究，甚至是老鼠MR模型 已发表了偏心肥大和心肌功能障碍的机理 严重的MR尚不清楚。因此，该项目的总体目标是了解LV的机械基础 继发于严重MR的收缩功能障碍可以指导新的治疗策略的发展。在 当前的建议，我们开发了MR的第一个小鼠模型。瓣膜破坏是通过切断来实现的 超声心动图证实了使用虹彩切除术剪刀和严重MR的MV小叶和和弦。我们 发现该模型概括了严重MR对人体心肌的影响 肥大，收缩功能障碍和规范肥大途径的激活。此外，我们发现 定向细胞生长激活作为纵向心肌细胞生长的可能机制的证据 回应MR。因此，我们假设MR诱导的偏心心肌细胞肥大是 通过与方向性细胞生长结合的典型肥大途径的激活介导。有 三个目的：确定氧化DNA损伤在调节偏心心肌细胞肥大中的作用 对严重MR的反应。确定CRB2在产后调节心肌细胞形状中的作用 发育并响应肥厚刺激。最后，我们旨在确定 响应MR的心肌细胞肥大期间的肌膜mRNA翻译。