Shear stress, SIRT1, and Arterial Stiffening

剪切应力、SIRT1 和动脉硬化

基本信息

批准号：
8145200
负责人：
John YJ Shyy
金额：
$ 38万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8145200
关键词：
5&apos -AMP-activated protein kinase Ablation Affect Age Aging Aging-Related Process Arteries Attenuated Biological Availability Blood Vessels Blood flow Ca(2+)-Calmodulin Dependent Protein Kinase Calcium/calmodulin-dependent protein kinase Cardiovascular Diseases Cells Cellular Stress Response Clinical Clinical Research Coculture Techniques Collagen Coronary heart disease Elasticity Elastin Endothelial Cells Endothelium Etiology Event Exhibits Extracellular Matrix Gene Expression Heart Diseases Histone Deacetylase Homologous Gene Hypertrophy Impairment Knock-out Knockout Mice Left Ventricular Hypertrophy Longevity Mammalian Cell Mammals Mating Types Measures Mechanics Molecular Molecular Profiling Mus Nitric Oxide Oxidative Stress Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Phosphorylation Phosphotransferases Physiologic pulse Prevention Property Pulsatile Flow Pulse Pressure Reactive Oxygen Species Regulation Research Risk Factors Role Signal Transduction Smooth Muscle Myocytes Stimulus Stroke System Testing Transgenic Mice Vascular Endothelial Cell Vasodilation Yeasts age related anti aging base biological adaptation to stress cardiovascular risk factor gain of function hemodynamics human NOS3 protein in vivo mouse model novel overexpression oxidation public health relevance research study response shear stress spatiotemporal

项目摘要

DESCRIPTION (provided by applicant): Arterial stiffening, manifested by thickening and reduced elasticity of conduit arteries, is an independent risk factor for stroke and heart disease. Although the etiology of arterial stiffening correlates well with aging, the underlying cellular and molecular basis remains unclear. In vivo, hemodynamic forces dynamically act on the vascular wall, which greatly affect arterial function and mechanical properties. Arterial stiffening may involves aberrant endothelial response to shear stress resulted from these hemodynamic forces. We recently found that SIRT1, an anti-aging regulator is modulated by shear stress in vascular endothelial cells (ECs). Moreover, calmodulin-dependent protein kinase (CaMKK) appears to be a shear stress-sensitive kinase that regulates SIRT1. We thus hypothesize that shear stress upregulates SIRT1 in the endothelium of conduit arteries, which ameliorates pathophysiological remodeling leading to arterial stiffening. At the upstream, CaMKKb is activated in response to the physiologically relevant shear stress. As a consequence of the activated CaMKKb-SIRT1 pathway, the endothelial nitric oxide synthase (eNOS)-derived NO bioavailability and PGC-1a-regulated ROS scavenger expression are augmented. Thus, the advantageous effects of shear stress-augmented SIRT1 include decreased oxidative stress and remodeling of extracellular matrices. To test our hypothesis, three Specific Aims are proposed. Specific Aim 1 will examine the hemodynamic factors critical for the induction of SIRT1 in cultured ECs. Molecular signaling experiments will then be conducted to study the mechanism by which CaMKKb regulates SIRT1 in ECs responding to the defined shear stress. Specific Aim 2 will elucidate the cellular and molecular mechanisms by which shear stress-induced SIRT1 exerts anti- stiffening effects in an EC/vascular smooth muscle cell co-culture system. We will decipher the synergistic effect of SIRT1 and AMP-activated protein kinase (AMPK) in eNOS-derived NO bioavailability and PGC-1a-regulated reactive oxygen species (ROS) scavengers. Specific Aim 3 will investigate the role of shear stress-activated SIRT1 in arterial stiffening in mouse models. Specifically, we will compare the spatiotemporal changes of arterial stiffening in EC-sirt1-/- knockout, Tg-EC-sirt1, and CaMKKb-/- mice. The arterial stiffening-associated changes in hemodynamic factors, aortic wall remodeling, and gene expression profiles will be measured and correlated. Results from these proposed studies, if as anticipated, will help to understand the mechano and molecular basis of arterial stiffening. PUBLIC HEALTH RELEVANCE: Arterial stiffening, associated with the aging process, is an independent risk factor for many cardiovascular diseases. SIRT1 is a master regulator involved in many anti-stress responses and we recently found that hemodynamic force can activate SIRT1 in vascular cells. This proposed study will investigate the mechano and molecular basis of flow induction of SIRT1, which would be anti-arterial stiffening. The proposal will significantly increase our understanding of mechanisms by which blood flow interplays with aging process in arterial stiffening. Results from the proposed experiments are likely to contribute to novel therapies for its prevention and/or treatment.

描述（由申请人提供）：动脉硬化，表现为导管动脉增厚和弹性降低，是中风和心脏病的独立危险因素。尽管动脉硬化的病因与衰老密切相关，但其潜在的细胞和分子基础仍不清楚。在体内，血流动力动态地作用于血管壁，极大地影响动脉功能和机械特性。动脉硬化可能涉及内皮细胞对这些血流动力学力引起的剪切应力的异常反应。我们最近发现 SIRT1（一种抗衰老调节因子）受到血管内皮细胞 (EC) 剪切应力的调节。此外，钙调蛋白依赖性蛋白激酶 (CaMKK) 似乎是一种调节 SIRT1 的剪切应力敏感激酶。因此，我们假设剪切应力上调导管动脉内皮中的 SIRT1，从而改善导致动脉硬化的病理生理重塑。在上游，CaMKKb 响应生理相关的剪切应力而被激活。 CaMKKb-SIRT1 通路激活后，内皮一氧化氮合酶 (eNOS) 衍生的 NO 生物利用度和 PGC-1a 调节的 ROS 清除剂表达增强。因此，剪切应力增强的 SIRT1 的有利作用包括减少氧化应激和重塑细胞外基质。为了检验我们的假设，提出了三个具体目标。具体目标 1 将检查对培养 EC 中诱导 SIRT1 至关重要的血流动力学因素。然后将进行分子信号实验来研究 CaMKKb 调节 ECs 中 SIRT1 响应定义的剪切应力的机制。具体目标 2 将阐明剪切应力诱导的 SIRT1 在 EC/血管平滑肌细胞共培养系统中发挥抗硬化作用的细胞和分子机制。我们将破译 SIRT1 和 AMP 激活蛋白激酶 (AMPK) 在 eNOS 衍生的 NO 生物利用度和 PGC-1a 调节的活性氧 (ROS) 清除剂中的协同作用。具体目标 3 将研究剪切应力激活的 SIRT1 在小鼠模型动脉硬化中的作用。具体来说，我们将比较 EC-sirt1-/- 敲除小鼠、Tg-EC-sirt1 和 CaMKKb-/- 小鼠的动脉硬化时空变化。将测量并关联与动脉硬化相关的血流动力学因素、主动脉壁重塑和基因表达谱的变化。如果正如预期的那样，这些拟议研究的结果将有助于了解动脉硬化的力学和分子基础。公众健康相关性：与衰老过程相关的动脉硬化是许多心血管疾病的独立危险因素。 SIRT1是参与许多抗应激反应的主要调节因子，我们最近发现血流动力学可以激活血管细胞中的SIRT1。这项拟议的研究将研究 SIRT1 血流诱导的力学和分子基础，这将是抗动脉硬化的。该提案将显着增加我们对动脉硬化中血流与衰老过程相互作用机制的理解。所提出的实验结果可能有助于为其预防和/或治疗提供新的疗法。