老年心脏对缺血再灌注损伤（I/RI）更为敏感，损伤加重，而机制不清楚。我们前期工作发现，与老年野生型小鼠相比， Rap1基因敲除小鼠的心脏中，p53的表达显著增加，而PGC1α水平明显降低，表现出更明显的心脏重塑，功能障碍，以及心脏线粒体缺陷。由此我们推测，随着衰老，Rap1可能通过p53依赖或非依赖性地通路调控PGC1α表达。在Rap1缺乏时，PGC1α水平也将被抑制。降低的PGC1α水平将导致线粒体生物合成降低，产生功能障碍，包括线粒体脂代谢降低，ATP生成减少，氧化磷酸化受损以及活性氧自由基增加，从而导致心脏功能受损和结构改变，并增加对心肌I/RI的敏感性。我们拟通过Rap1基因敲除及过表达，使用不同年龄段小鼠，通过在体心肌I/RI、干扰p53及PGC1α表达实验、小鼠原代心肌细胞缺氧/复氧实验，验证上述假说，为I/RI、尤其是老年心脏中的治疗和预后提供新的实验及理论依据。

Ischemic heart disease (IHD) caused by partial or complete blockage of coronary arteries is a leading cause of morbidity and mortality worldwide. Clinically, the most effective intervention to reduce ischemic injury is restoration of blood flow, but reperfusion itself may cause additional injury called “ischemia/reperfusion injury (I/RI)”. The aging heart is more vulnerable to ischemic injury. Although the mechanism is still largely unknown, mitochondria alterations in aging heart have been suggested to play an important role in its pathology. With aging, the heart exhibits reduced adenosine triphosphate generation, increased reactive oxygen species, impaired oxidative phosphorylation and decreased mitochondrial biogenesis. These mitochondrial defects lead to cardiac remodeling and dysfunction, further increasing aging heart susceptibility to I/RI. Thus, identifying a potential central controller that reverses mitochondrial defects may provide new strategy to combat I/RI in aging heart..The telomeric protein repressor activator protein 1 (Rap1) is essential for the maintenance of telomere length and structural integrity. In the absence of telomerase, Rap1 knockout mice display more pronounced telomere shortening and increased expression of p53 (the senescence marker) when compared with counterparts. Of note, p53 can directly bind to the promoter of PGC1α and suppress its expression at transcriptional level. PGC1α, the coactivator of PPARγ, has been demonstrated to drive virtually all aspects of mitochondrial biogenesis and function and its enhancement protects against myocardial I/RI. Furthermore, Rap1 can bind to PGC1α loci in the liver, and regulate transcription of PGC1α. Indeed, our preliminary studies indicate that in aged mice, Rap1 deficiency leads to pronounced mitochondrial dysfunction, cardiac dysfunction, with concomitantly enhanced p53, reduced PGC1α level and increased susceptibility to myocardial I/RI when compared to age-matched counterparts. We therefore postulate that in aging heart, which partly mimics the defective telomerase, Rap1 deficiency may down-regulate the expression of PGC1α in p53-dependent and -independent pathways, and thereby lead to mitochondrial dysfunction and increased susceptibility to myocardial I/RI. The proposed research aims, therefore, to .1..Investigate if Rap1 deficiency increases the susceptibility to myocardial I/RI in aging heart;.2..Determine whether or not Rap1 deficiency precipitates cardiac aging and increases the susceptibility of aging heart to I/RI via p53-PGC1α signaling..The proposed work will improve our understanding on the telomere-associated protein Rap1, which forges a link between telomere homeostasis and mitochondrial function during aging and may help facilitate the development of better therapies for the management of IHD in elderly in whom this disease is very common.