Nuclear Mechanisms of VSMC Gene Regulation and Cellular Interactions in Diabetes

描述（由申请人提供）：心血管并发症如高血压和动脉粥样硬化在糖尿病人群中非常普遍。证据支持与血管炎症相关的基因在糖尿病血管疾病发病机制中的作用。然而，对于在血管平滑肌细胞（VSMC）中调控这些基因的微妙分子机制或关键核因子，以及它们在体内的功能相关性，我们知之甚少。最近的研究表明，糖尿病血管并发症在没有进行过强化血糖控制的患者中继续发展。基于我们新的支持性数据，我们提出血管细胞中基因调控的新的“表观遗传”染色质重塑机制可能介导这种“糖尿病记忆”现象。我们的数据还表明，在体外或体内糖尿病条件下，通过这些核机制在VSMC中激活的基因可以导致VSMC与内皮下空间单核细胞之间的密切相互作用。我们的中心假设是，糖尿病刺激如高糖（HG）和晚期糖基化终产物（AGEs）通过新的体内核染色质重塑机制诱导VSMC中的炎症趋化因子和细胞因子。这些因素可诱发血管炎症、vsmc -单核细胞相互作用和表型改变，从而加速心血管疾病的发生。

DESCRIPTION (provided by applicant): Cardiovascular complications such as hypertension and atherosclerosis are highly prevalent in the diabetic population. Evidence supports a role for genes associated vascular inflammation in the pathogenesis of diabetic vascular disease. However, very little is known about the subtle molecular mechanisms or key nuclear factors involved in regulating these genes in vascular smooth muscle cells (VSMC), or their in vivo functional relevance. Recent studies show that diabetic vascular complications continue to progress in patients who have not had prior intensive glycemic control. Based on our new supportive data, we propose that novel "epigenetic" chromatin remodeling mechanisms of gene regulation in vascular cells may mediate this "diabetic memory" phenomenon. Our data also demonstrate that genes activated in VSMC under diabetic conditions in vitro or vivo via these nuclear mechanisms can lead to close interactions between VSMC and monocytes in the subendothelial space. Our central hypothesis is that diabetic stimuli such as high glucose (HG) and advanced glycation end products (AGEs) induce inflammatory chemokines and cytokines in VSMC via novel in vivo nuclear chromatin remodeling mechanisms. These factors can induce vascular inflammation, VSMC-monocyte interactions and phenotypic changes and thereby lead to accelerated cardiovascular disease. Specific Aim 1 is to examine the nuclear transcriptomic mechanisms by which diabetic stimuli lead to chemotactic gene expression in VSMC. Here we will determine the nuclear interplay between NF-kB transcription factor and key chromatin factors using gain- and loss-of-function approaches. Specific Aim 2 is to evaluate the in vivo relevance of these nuclear mechanisms and factors in VSMC and aortas derived from mouse models of diabetes. Here we will determine the potential association with hyperglycemic memory, sustained gene expression and activation observed in these diabetic cells. Specific Aims 3 and 4 are to determine the functional impact of diabetic and atherosclerotic conditions, and these chromatin changes in leading to vascular dysfunction by promoting heterotypic interactions between VSMC and monocytes in vitro and in the aortas of mouse models. Our preliminary results have uncovered novel hitherto unexplored vascular mechanisms of action of diabetic stimuli. Our state-of-the-art transcriptomic approaches in this proposal could significantly advance the field and make a key impact by unraveling new factors and mechanisms underlying the sustained vascular complications of diabetes. The completed results could provide strategies for the development of sorely needed newer and novel therapies to reduce the morbidity and mortality of diabetic cardiovascular disease.