脂联素及其多聚化在败血性心肌病中的作用与机制

Sepsis is one of the main consequences of infectious diseases and the chief cause of death in ICU. Sepsis-induced myocardial dysfunction is one of the major predictors of morbidity and mortality of sepsis. Unfortunately, studies for the past 30 years have been unable to develop an efficient therapy for sepsis-mediated cardiomyopathy and better understanding the underlying mechanisms and identification of novel targets of septic cardiomyopathy are thus critical for the prevention and treatment of this disease. Our preliminary data showed that the total level of serum adiponectin in septic mice was significantly decreased. In addition, adiponectin deficiency led to more severe cardiac depression in septic mice. Taken together, these findings suggest a potential protective role of adiponectin in septic cardiomyopathy. Since the high molecular weight (HMW) form of adiponectin has been shown to be the most active form of the protein. We therefore hypothesize that adiponectin and its HMW multimer play a protective role in septic cardiomyopathy. This study is focused on the role of adiponectin in septic cardiomyopathy and mechanisms of action of adiponectin. Our study will demonstrate information for the first time whether altering the stability and miltimerization of endogenous adiponectin play a role in LPS-induced cardiac depression. The completion of this study should open up opportunities for the development of new drugs for septic cardiomyopathy.

败血症是血液微生物感染引起的全身炎症反应综合征，是ICU危重病人的主要死亡原因之一。败血性心肌病是败血症的常见并发症，也是败血症发病和死亡的最主要原因之一。遗憾的是，目前败血性心肌病的治疗尚无有效药物。因此，阐明其发病机制，寻找新的治疗靶点，对于败血性心肌病的防治具有重要的科学和临床意义。我们前期研究结果显示，脂联素水平在败血症过程中显著下降，且脂联素敲除可显著加剧败血症小鼠的心脏损伤。此外，大量研究证明，高分子量（HMW）脂联素是最具生物学活性的多聚体形式，且有研究发现败血症病人的HMW脂联素有明显下降。因此，我们假设，脂联素尤其是HMW脂联素可能对败血性心肌病具有保护作用。本课题将国际上首次利用独特的脂肪特异性DsbA-L过表达或敲除的小鼠模型，通过调控内源性脂联素稳定性及其多聚化水平，深入揭示脂联素尤其是HMW脂联素在败血性心肌抑制中的作用及机制，为治疗败血性心肌病提供新靶点和新思路

脓毒血症是血液微生物感染引起的全身炎症反应综合征，是ICU危重病人的主要死亡原因之一。脓毒性心肌病是脓毒血症最常见的并发症，也是脓毒血症死亡的主要原因之一，而目前临床上尚无有效治疗脓毒性心肌病的药物。因此，阐明其发病机制，寻找新的治疗靶点和治疗方法对于脓毒性心肌病的防治具有重要的科学和临床意义。我们的研究发现，北美人参可保护脓毒性心肌病的发生发展，其作用机制与抑制心肌NOX2-ERK1/2信号和TNF-alpha的表达有关，提示北美人参具有防治脓毒性心肌病的治疗潜力。同时，我们的工作有助于更深入地了解这种广泛使用的药草的作用机理及应用前景。