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Effects of age and immune dysfunction on the cardiac extracellular matrix and diastolic function.

机译：年龄和免疫功能障碍对心脏细胞外基质和舒张功能的影响。

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摘要

Cardiomyopathy is defined as CVD affecting the gross structure of the myocardium and represents a significant portion of CVD. Cardiomyopathies are often initiated by diastolic dysfunction which can be fatal, even in the absence of systolic dysfunction. Currently, treatment of diastolic dysfunction remains empirical with an emphasis on prevention. This dissertation is focused on the mechanism of cardiomyopathy and diastolic dysfunction during aging and immune dysfunction. The governing hypothesis of this dissertation is that altered cytokine release such as that seen during aging and immune dysfunction is capable of causing diastolic dysfunction in the form of fibrosis and left ventricular stiffness. We hypothesized that reversal of immune dysfunction is a potential therapeutic mechanism to reverse diastolic dysfunction. Our first study examined the role of aging and immunose nescence on the cardiac extracellular matrix and left ventricular stiffness. We demonstrated age-related immune dysfunction, myocardial fibrosis, and diastolic dysfunction. We also found that exogenous dehydroepiandrosterone (DHEA), an adrenal steroid hormone popular due to its anti-aging effects, at least partially reversed each of these pathologies in aged mice. In this model, fibrosis and its reversal were strongly associated with alterated regulation of matrix metal loproteinases and collagen cross-linking. We proposed two mechanisms for the protective effects of DHEA: (1) a direct effect on cardiac fibroblasts, or (2) downstream effects of immune modulation. In the subsequent study on the effects of DHEA, we found that DHEA is capable of directly altering cardiac fibroblast function, suggesting a mechanism for the effects of DHEA on cardiac function in vivo. Interestingly, we also demonstrated age-related functional changes in cardiac fibrolasts. Due to pleiotropic effects of DHEA, we then decided to specifically target the immune system using novel T-cell receptor peptides during murine AIDS (mAIDS). Mice with mAIDS suffer from cardiomyopathy in the absence of myocarditis and opportunistic pathogens. Further, these mice have dramatic immune dysfunction that can be reversed with these T-cell receptor peptides. We demonstrated that reversal of immune dysfunction in mAIDS mice was associated with reversal of myocardial fibrosis and ventricular stiffness. In conclusion, we have demonstrated age- and immune-related diastolic dysfunction that can be reversed by modulation of the T-cells of the immune system. We feel that immune modulation should be further investigated as a therapeutic target to treat diastolic dysfunction during immune dysfunction. We also found that MMPs and collagen cross-linking are highly involved in extracellular matrix regulation in the models used in this dissertation.
机译：心肌病定义为影响心肌总体结构的CVD，是CVD的重要组成部分。心肌病通常是由舒张功能障碍引发的，即使没有收缩功能障碍，也可能是致命的。当前，舒张功能障碍的治疗仍是经验性的，重点在于预防。本文主要研究衰老过程中的心肌病和舒张功能障碍以及免疫功能障碍的机制。本论文的主要假设是，诸如衰老和免疫功能异常期间所见的细胞因子释放改变，能够以纤维化和左心室僵硬的形式引起舒张功能障碍。我们假设免疫功能障碍的逆转是逆转舒张功能障碍的潜在治疗机制。我们的第一项研究探讨了衰老和免疫衰老对心脏细胞外基质和左心室僵硬的作用。我们证明了与年龄有关的免疫功能障碍，心肌纤维化和舒张功能障碍。我们还发现，外源性脱氢表雄酮（DHEA）是一种肾上腺类固醇激素，由于其抗衰老作用而广受欢迎，至少可以部分逆转衰老小鼠中的每种病理。在该模型中，纤维化及其逆转与基质金属蛋白酶和胶原交联的改变调控密切相关。我们提出了两种DHEA保护作用的机制：（1）对心脏成纤维细胞的直接作用，或（2）免疫调节的下游作用。在随后的DHEA作用研究中，我们发现DHEA能够直接改变心脏成纤维细胞的功能，提示DHEA在体内对心脏功能的作用机制。有趣的是，我们还证明了心脏成纤维细胞中与年龄相关的功能变化。由于DHEA的多效作用，我们决定在鼠艾滋病（mAIDS）期间使用新型T细胞受体肽特异性靶向免疫系统。在没有心肌炎和机会性病原体的情况下，患有mAIDS的小鼠患有心肌病。此外，这些小鼠具有严重的免疫功能障碍，可以用这些T细胞受体肽逆转。我们证明，mAIDS小鼠免疫功能障碍的逆转与心肌纤维化和心室僵直的逆转有关。总之，我们已经证明了与年龄和免疫有关的舒张功能障碍，可以通过调节免疫系统的T细胞来逆转。我们认为，应进一步研究免疫调节作为治疗功能障碍期间舒张功能障碍的治疗靶点。我们还发现，在本文使用的模型中，MMP和胶原蛋白的交联高度参与细胞外基质的调控。

著录项

  • 作者

    Alwardt, Cory M.;

  • 作者单位

    The University of Arizona.;

  • 授予单位 The University of Arizona.;
  • 学科 Biology Animal Physiology.; Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 131 p.
  • 总页数 131
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生理学;预防医学、卫生学;
  • 关键词

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