Innate Immunity and Cardiovascular Function

描述(由申请人提供)：高血糖会导致心血管并发症，并增加发病率和死亡率。蛋白激酶C、多元醇和晚期糖基化终末产物(AGE)通路被认为是高血糖引起的血管功能障碍(即内皮依赖性松弛丧失)和心肌病(即左心功能不全、肥厚和心肌纤维化)的罪魁祸首。这三条通路的一个共同特征是产生了活性氧，我们证明在缺血/再灌注(I/R)模型中，这与甘露糖结合凝集素(MBL)配体的表达有关。我们最近描述了急性高血糖小鼠心肌I/R后心脏损伤的扩大。此外，野生型(WT)小鼠的急性高血糖导致心脏前体细胞的损失和左心室肥厚的发展。在MBL基因缺失的小鼠中，这种急性高血糖模型中由高血糖引起的心脏异常完全逆转。在这项研究中，我们证明了缺乏MBL复合体或补体抑制可以消除急性高血糖后心脏纤维蛋白生成、血管功能障碍和炎症的几个关键因素。这项资助将描述每种补体途径(经典途径、替代途径、凝集素途径和末端途径)在急性高血糖引起的血管病变和心肌病中的作用。我们还将描述MBL复合体和补体在肾素-血管紧张素系统(RAS)激活和心脏自噬中的作用。虽然心脏自噬可以是适应性的，也可以是非适应性的，但对高血糖时的心脏自噬知之甚少，也没有研究过与补体的相互作用。我们认为补体激活导致心脏自噬，代表了促纤维化介质产生的集中联系，包括RAGE、转化生长因子-21和半乳糖凝集素-3。这一建议将继续我们实验室对补体系统和心肌功能的总体关注，通过研究急性高血糖时易患血管病变和心肌病的分子机制。此外，这些特定的目标可能随后导致改善风险分层、资源利用，以及开发新的抗补体疗法以预防高血糖心血管并发症。

DESCRIPTION (provided by applicant): Hyperglycemia induces cardiovascular complications associated with increased morbidity and mortality. The protein kinase C, polyol, and advanced glycation end products (AGE) pathways are thought to be responsible for hyperglycemia-induced vascular dysfunction (i.e., loss of endothelium-dependent relaxation) and cardiomyopathy (i.e., left ventricular dysfunction, hypertrophy and cardiac fibrosis). A common feature of these three pathways is the production of reactive oxygen species, which we showed to be responsible for mannose binding lectin (MBL) ligand expression in ischemia/reperfusion (I/R) models. We recently described augmented cardiac injury in acute hyperglycemic mice following myocardial I/R. Further, acute hyperglycemia in wild type (WT) mice caused a loss of cardiac progenitor cells and the development of left ventricular hypertrophy. Hyperglycemia-induced cardiac abnormalities in this acute hyperglycemia model were completely reversed in MBL null mice. In the present grant, we demonstrate that the absence of the MBL complex or complement inhibition eliminates several key factors involved in the cardiac fibrinogenesis, vascular dysfunction, and inflammation following acute hyperglycemia. This grant will characterize the role of each complement pathway (classical, alternative, lectin and terminal) in the vasculopathy and cardiomyopathy induced by acute hyperglycemia. We will also characterize the involvement of the MBL complex and complement in renin-angiotensin system (RAS) activation and cardiac autophagy. While cardiac autophagy can be adaptive or maladaptive, little is known about cardiac autophagy in hyperglycemia and no interactions with complement have been investigated. We propose that complement activation leads to cardiac autophagy and represents a centralized nexus for pro-fibrotic mediator production including RAGE, TGF-21 and galectin- 3. This proposal will continue our laboratory's general focus on the complement system and myocardial function by investigating the molecular mechanisms that predispose individuals to vasculopathy and cardiomyopathy during acute hyperglycemia. Furthermore, these specific aims may subsequently lead to improved risk stratification, resource utilization, and the development of novel anti-complement therapies to protect against hyperglycemic cardiovascular complications.