Improving post-surgery recovery of failing hearts by targeting cardiomyocyte senescence

总结：在过去的十年中，随着医学治疗和外科干预的进步， 患有心力衰竭（HF）的患者已经得到改善，但是大量患者仍然进展到终末期HF， 治疗选择主要限于心脏移植。随着患者对移植的需求不断增加， 超过器官供应，需要新的方法来了解HF进展背后的机制 并开发新的治疗方法来延缓或阻止其发展。冠状动脉等外科手术 旁路移植术和心室辅助装置植入，高龄患者（65岁以上）经常显示 尽管完成了血运重建和心脏卸载，但恢复较差。这背后的原因 病理过程尚未完全了解，但已认识到心脏老化有助于 对这种病理结果有很大影响。最近的研究表明，衰老的心脏积累衰老 心肌细胞分泌促炎细胞因子、趋化因子和生长因子，称为SASP （衰老相关分泌表型）。SASP在破坏母细胞的同时， 邻近的成纤维细胞转化成肌成纤维细胞，导致进行性心脏纤维化和HF。许多 先前的报道表明，消除衰老细胞可以减轻衰老相关疾病，包括 癌症、肾衰竭、肺纤维化和肌肉骨骼疾病。然而，心肌细胞的作用 进行性心室纤维化的衰老和衰竭心脏的术后恢复从未研究过。我 实验室正在研究sirtuin类似物Sirt6，它可以延长小鼠的寿命。我们发现Sirt6水平降低 在衰老的心脏和HF的发展过程中。在心肌细胞中，Sirt6缺失诱导p53和p16INK4a 表达和线粒体破坏，衰老的标志物。我们还发现心肌细胞SASP 激活成纤维细胞转化成肌成纤维细胞。这些发现促使我们提出假设， Sirt6有可能阻断心肌细胞衰老和SASP介导的成纤维细胞合成 细胞外基质过多因此，通过增加Sirt6，我们可以防止进行性 心脏纤维化和改善接受手术干预的衰竭心脏的术后恢复。为了验证这一 假设，我们开发了两个转基因小鼠品系，其中Sirt6在小鼠中特异性过表达， 心肌细胞或在所有组织中。我们将从三个方面来检验这一假设。目标1：研究Sirt6是否 激活阻断心肌细胞衰老和成纤维细胞激活，以及进行性心脏病的发展。 在HF小鼠模型中的纤维化。目的2：确定Sirt6下调的潜在机制， Sirt6阻断心肌细胞衰老的机制。目的3：测试Sirt6的翻译潜力 激活剂，以保护老化的心脏免受心肌细胞衰老和损伤后进行性 心脏纤维化和HF。我们相信，通过完成这些目标，我们将确定为什么衰老的基本机制， 心脏对手术后恢复的反应很差，一种新的疗法可以改善它。

Summary: In the last decade, with advancements in medical therapies and surgical interventions survivability of patients with heart failure (HF) has improved, but a significant number of patients still progress to end-stage HF, where treatment options largely limited to cardiac transplantation. As patients demand for transplant continue to exceed the organ supply, new approaches needed to understand the mechanism behind the progression of HF and to develop new therapies to delay or prevent its development. With surgical interventions like coronary artery bypass grafting and ventricular assist device implantation, patients with advanced age (65+ years) often show inferior recovery despite complete revascularization and unloading of the heart. The underlying cause of this pathologic process not yet completely understood, but it has been realized that cardiac aging contributes significantly to this pathologic outcome. Recent studies indicate that aging hearts accumulate senescent cardiomyocytes, which secrete pro-inflammatory cytokines, chemokines and growth factors, known as SASP (senescence-associated secretory phenotype). While SASP causes destruction of the parent cell, it also activates neighboring fibroblasts to transform into myofibroblasts, leading to progressive cardiac fibrosis and HF. Many previous reports demonstrated that elimination of senescent cells mitigates aging-associated diseases, including cancer, renal failure, pulmonary fibrosis and musculoskeletal diseases. However, a role of cardiomyocyte senescence in progressive ventricular fibrosis and post-surgery recovery of failing hearts never studied. My laboratory is working on a sirtuin analogue Sirt6, which extends lifespan of mice. We found reduced Sirt6 levels in aging hearts and during development of HF. In cardiomyocytes Sirt6 depletion induced p53 & p16INK4a expression and mitochondrial destruction, markers of senescence. We also found that cardiomyocyte SASP activates fibroblasts to transform into myofibroblasts. These findings prompted us to propose the hypothesis that Sirt6 has potential to block cardiomyocyte senescence and SASP-mediated activation of fibroblasts to synthesize excessive extracellular matrix. Therefore, by augmenting Sirt6, we can prevent development of progressive cardiac fibrosis and improve post-surgery recovery of failing hearts undergoing surgical interventions. To test this hypothesis, we developed two transgenic mouse lines, in which Sirt6 overexpressed either specifically in cardiomyocytes or globally in all tissues. We will test this hypothesis in three aims. Aim 1: Study whether Sirt6 activation blocks cardiomyocyte senescence and fibroblast activation, and development of progressive cardiac fibrosis in the mouse models of HF. Aim 2: Determine the underlying mechanism of Sirt6 downregulation and the mechanism by which Sirt6 blocks cardiomyocyte senescence. Aim 3: test the translational potential of a Sirt6 activator to protect the aging heart from developing cardiomyocyte-senescence and post-injury progressive cardiac fibrosis and HF. We believe by completing these aims, we will determine a basic mechanism of why aging hearts respond poorly to post-surgery recovery, and a new therapy to improve it.