Role of bioactive lipids in the protective pathways of obesity in ischemic cardi

肥胖在西方世界已接近流行状态，是急性心肌梗死的已知危险因素。 心肌梗死（AMI）。AMI和随后的缺血性心脏病（IHD）通常并发高血压， 尽管在药物治疗和血运重建方面取得了显著进展， 战略布局目前，由于心脏移植的遗传局限性， 替代梗死心肌的治疗策略和疗法主要是姑息性的。巧合的是， 肥胖也可赋予对导致IHD的AMI相关重塑的保护作用。的 对这种保护作用的分子基础知之甚少。急性心肌梗死引发了人们知之甚少的先天性修复 BMSPC被动员并向缺血心肌归巢的机制 有助于心肌再生并与心脏恢复相关。我们的初步数据显示 生物活性脂质，如鞘氨醇-1磷酸（SIP），而不是传统的趋化因子， 在这场动员和归巢中扮演着典型的角色。有趣的是，肥胖和相关的代谢 综合征与生物活性脂质代谢的改变有关。我们申请的目的， 因此，更好地了解AMI诱导的干细胞中与肥胖相关的变化 动员途径，特别是那些涉及生物活性脂质，并设计治疗， 治疗性心肌再生策略的方法。我们的核心假设已经被明确表述为 基于现有的文献和我们强有力的初步数据表明，BMSPC表达SIP 受体，并将以SIP依赖性方式从AMI患者向血浆迁移。我们的理由是 这些研究是，了解生物活性脂质和干细胞动员的保护作用， AMI在肥胖中的应用将有助于建立一个强有力的科学框架， 心肌再生的临床试验利用现有的和新的药理学调节剂的生物活性 脂质及其受体。除了临床研究，我们的方法将利用小分子策略， 通过检查肥胖相关的分子和细胞途径，特别是那些 涉及由心肌梗死激活的生物活性脂质（目的1）;并检查 生物活性脂质的代谢和受体表达促进AMI后心脏恢复（目的2）。

Obesity is approaching epidemic state in the western worid and is a known risk factor for acute myocardial infarction (AMI). AMI and the subsequent ischemic heart disease (IHD) are often complicated with high mortality and poor overall prognosis despite significant advances in medical therapy and revascularization strategies. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infracted myocardium and therapies are largely palliative. Paradoxically, obesity may also confer a protective effect against AMI-associated remodeling which leads to IHD. The molecular kiasis for this protection is poorly understood. AMI initiates poorly understood innate reparatory mechanisms through which BMSPCs are mobilized and home towards the ischemic myocardium contributing to myocardial regeneration and correlating with cardiac recovery. Our preliminary data indicates that bioactive lipids such as sphingosine-1 phosphate (SIP), but not traditional chemokines, play a quintessential role in this mobilization and homing. Interestingly, obesity and the associated metabolic syndrome are associated with alterations in bioactive lipids' metabolism. Our objective in this application, therefore, is to develop better understanding ofthe obesity-associated alterations in AMI-induced stem cell mobilization pathways, specially those involving bioactive lipids, and devise therapies that hamess this process for therapeutic myocardial regeneration strategies. Our central hypothesis has been formulated based upon the existing literature and our strong preliminary data demonstrating that BMSPCs express SIP receptors and will migrate towards plasma from AMI patients in an SI P dependent fashion. Our rationale for these studies is that understanding the protective role of bioactive lipids and stem cell mobilization during AMI in obesity would help establish a strong scientific framework for eventual generalizable human myocardial regenerative clinical trials utilizing the available and new pharmacological modulators of bioactive lipids and their receptors. In addition to clinical studies, our approach will exploit small molecule-strategies in mouse models through examining the obesity associated molecular and cellular pathways, specially those involving bioactive lipids, that are activated by myocardial infarction (Aim 1); and examine the modulation of bioactive lipids' metabolism and receptor expression to enhance cardiac recovery following AMI (Aim 2).