Damage to arterial extracellular matrix induced by reactive nitrogen species and its consequences

众所周知，在动脉粥样硬化(动脉硬化)的发展过程中，脂质会在动脉壁中积聚，而这些脂质中的大部分来自低密度脂蛋白(LDL)。存在于动脉壁中的细胞从低密度脂蛋白中摄取胆固醇和脂肪的过程通常受到严格的调控和反馈控制，但低密度脂蛋白颗粒的修饰可以导致巨噬细胞的清道夫受体识别它们，并在这些细胞中无规律地积累脂质。这些富含脂质的(泡沫)细胞的形成是动脉粥样硬化的一个标志。虽然这种脂质堆积是不可取的，但如果由此产生的损害是稳定的，它们比那些不稳定和容易破裂的损害更不值得关注。病变破裂和随之而来的血液凝块形成(血栓形成)是心脏病猝死和中风的主要原因。尽管付出了相当大的努力，但斑块破裂的原因仍鲜为人知。这项研究将调查一种潜在的机制，通过这种机制，病变可能变得不稳定并容易破裂。我们将研究活性中间体在诱导细胞外基质损伤中的作用。已知的反应中间产物是由炎症细胞产生的，而且众所周知，这些细胞在病变中的水平升高。细胞外基质负责维持包括动脉壁在内的生物系统的三维结构，这种材料的损坏或碎裂可能会削弱这种支架，使病变容易破裂。我们还将研究这种基质损伤如何影响病变内细胞的行为。详细了解哪些过程在病变破裂中是重要的，这是开发新的治疗策略的基本前提。

It is well established that lipids accumulate in the artery wall during the development of atherosclerosis (hardening of the arteries), and that much of this lipid arises from low-density lipoproteins (LDL). The uptake of cholesterol and lipids from LDL by cells present in the arterial wall is normally tightly regulated and under feedback control, but modification of the LDL particles can result in their recognition by the scavenger receptors of macrophage cells and unregulated accumulation of lipids within such cells. The formation of these lipid-laden (foam) cells is a hallmark of atherosclerosis. Whilst this lipid accumulation is undesirable, if the resulting lesions are stable they are of less concern than those that are unstable and prone to rupture. Rupture of lesions and consequent blood clot formation (thrombosis) are a prime cause of sudden heart death and stroke. Despite considerable effort the reasons for plaque rupture are poorly understood. This study will investigate one potential mechanism by which lesions might become destabilised and prone to rupture. We will investigate the role of reactive intermediates in inducing damage to the extracellular matrix. Reactive intermediates are known to be generated by inflammatory cells, and it is well established that these cells are present at elevated levels in lesions. The extracellular matrix is responsible for maintaining the 3-dimensional structure of biological systems including the artery wall, and damage or fragmentation of this material may weaken this scaffolding and make the lesions prone to rupture. We will also examine how such matrix damage affects the behaviour of cells within lesions. A detailed knowledge of which processes are important in lesion rupture is an essential prerequisite to the development of new therapeutic strategies.