Role of peripheral endocannabinoid system in atherosclerosis

尽管心血管研究取得了重大进展，但动脉粥样硬化仍然是一个主要的健康负担，是全球死亡人数的主要原因。作为一种内源性脂质信号系统，所谓的内源性大麻素系统最近已演变为生理和病理生理过程中的重要调节因子。该系统至少包括两个不同的膜受体CB1和CB2，它们的内源配体(称为内源性大麻素)以及用于配体生物合成和失活的酶。我们和其他人已经表明，在动脉粥样硬化及其相关的心血管危险因素、肥胖、血脂异常、糖尿病和内皮功能障碍中，内源性大麻系统的活性增加。然而，内源性大麻素升高的原因以及CB1和CB2受体在动脉粥样硬化中的相反作用尚不清楚。这两种受体在中枢神经系统以及包括心血管系统在内的大多数外周器官中广泛表达，这一事实阻碍了基于全球受体缺乏的简单遗传方法。因此，很难剖析血管和免疫细胞CB1和CB2信号的具体作用。特定的目的：(1)基于骨髓嵌合体和细胞特异性突变，阐明血管和造血大麻素受体在动脉粥样硬化发病中的特定作用。(2)探讨内源性大麻素2-AG和内源性大麻素相关脂肪酸酰胺升高在动脉粥样硬化发病机制中的具体作用。(3)阐明这两种大麻素受体相互对立的病理生理效应的细胞内信号转导途径。这应该有助于促进我们目前对病理的理解，并有可能导致更有效和更具体的治疗方法和更好的心血管风险评估。

Despite major advances in cardiovascular research, atherosclerosis remains a major health burden and is responsible for the majority of all deaths worldwide. An endogenous lipid signaling system, the so-called endocannabinoid system has recently evolved as an important regulator in both physiological and pathophysiological processes. This system comprises at least two distinct membrane receptors, CB1 and CB2, their endogenous ligands (named endocannabinoids) as well as enzymes for ligand biosynthesis and inactivation. We and others have shown increased activity of the endocannabinoid system in atherosclerosis and its related cardiovascular risk factors, obesity, dyslipidemia, diabetes and endothelial dysfunction. However, the causal role of the elevated endocannabinoid tone and proposed opposing role of CB1 and CB2 receptors in atherosclerosis is not well understood. Simple genetic approaches based on global receptor deficiency are hampered by the fact that both receptors are widely expressed within the central nervous system as well as most peripheral organs, including the cardiovascular system. Thus, it is difficult to dissect the specific contribution of vascular and immune cell CB1 and CB2 signaling.Secific aims: (1) To clarify the specific role of vascular and hematopoietic cannabinoid receptors in the pathogenesis of atherosclerosis based on bone marrow chimeras and cell-specific mutation. (2) To investigate the specific contribution of elevated endocannabinoid 2-AG tone and endocannabinoid-related fatty acid amides in the pathogenesis of atherosclerosis (3) To shed light on the intracellular signaling pathways underlying the opposing pathophysiological effects of the two cannabinoid receptors.Based on this multi-disciplinary approach which combines cardiovascular biology, immunology and receptor biochemistry, we hope to gain a detailed view of the complex immunomodulatory and cardiometabolic effects of endocannabinoids that are key determinants of atherosclerosis. This should help advancing our current understanding of the pathology and potentially lead to more efficient and specific therapies and better cardiovascular risk assessment.