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

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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.