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The Application of Novel Metabolic Therapies to the Improvement of Cardiac Function and Architecture

机译：新型代谢疗法在改善心脏功能和结构方面的应用

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摘要

The vertebrate heart grows in response to increased contractile demands. However, as a largely post-mitotic cell type, cardiomyocytes are forced to grow in size, rather than replicate. This process is stimulated and maintained in two ways. First is in response to exercise and pregnancy, whereby cardiomyocytes undergo reversible hypertrophy in the absence of pathological gene expression and contractile dysfunction. Second is the pathological route to hypertrophy, which exposes the cardiomyocyte to metabolic stress and a strong risk for contractile dysfunction as well as death.;I have characterized mechanisms that induce physiological cardiac hypertrophy in the Burmese python following ingestion. In doing so, I found a subset of fatty acids that are elevated in the python plasma after a meal. These fatty acids are capable of inducing ventricular hypertrophy not only in the fasted python, but also in mice. This finding represents a potential supplement for exercise or therapeutic for diseases characterized by cardiomyocyte wasting or death, such as cachexia or dilated cardiomyopathy, respectively.;I also studied a genetic model of hypertrophic cardiomyopathy, which presents canonical features of heart disease and failure (e.g. fetal gene expression, ventricular dilation and contractile dysfunction). I found that the diseased heart displays profound metabolic deficiencies and a compensatory liver response. Rectifying cardiac metabolism (by reactivating metabolic regulators) or normalizing liver function (by inhibiting enhanced de novo glucose production) improves ventricular contractile function and architecture. By demonstrating that a complex metabolic network between organs significantly alters the progression of hypertrophic cardiomyopathy, this study may be helpful in guiding the development of alternative cardiac therapies.
机译：脊椎动物的心脏随着对收缩需求的增加而增长。但是，作为有丝分裂后的一种主要细胞类型，心肌细胞被迫增大大小，而不是复制。该过程可以通过两种方式来激发和维持。首先是对运动和妊娠的反应，心肌细胞在缺乏病理基因表达和收缩功能障碍的情况下经历可逆的肥大。第二个是肥大的病理学途径，它使心肌细胞暴露于代谢应激和收缩功能障碍以及死亡的强烈风险中。我已经研究了摄入后诱发缅甸蟒蛇生理性心肌肥大的机制。通过这样做，我发现一顿饭后蟒蛇血浆中脂肪酸含量升高。这些脂肪酸不仅能在禁食的蟒蛇中引起心室肥大，而且还能在小鼠中引起心室肥大。这一发现代表了一种运动或治疗潜在的补充剂，可分别用于治疗以心肌细胞消耗或死亡为特征的疾病，例如恶病质或扩张型心肌病。我还研究了肥厚型心肌病的遗传模型，该模型表现出心脏病和衰竭的典型特征（例如胎儿基因表达，心室扩张和收缩功能障碍）。我发现患病的心脏表现出严重的代谢缺陷和肝脏代偿性反应。纠正心脏代谢（通过重新激活代谢调节剂）或使肝功能正常化（通过抑制增强的从头葡萄糖生成）可改善心室收缩功能和结构。通过证明器官之间的复杂代谢网络会显着改变肥厚型心肌病的进展，这项研究可能有助于指导替代性心脏疗法的发展。

著录项

  • 作者

    Magida, Jason A.;

  • 作者单位

    University of Colorado at Boulder.;

  • 授予单位 University of Colorado at Boulder.;
  • 学科 Molecular biology.;Physiology.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 235 p.
  • 总页数 235
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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