免疫代谢与血管重塑-高同型半胱氨酸血症的作用

Immunometabolism and vascular remodeling-role of hyperhomocysteinemia

机体由于遗传缺陷造成甲硫氨酸代谢障碍或代谢其的肾脏转硫途径不足所导致的高同型半胱氨酸血症(hyperhomocysteinemia,HHcy)是心血管疾病的独立危险因素.免疫细胞高度依赖氧化代谢,其线粒体的致病突变阈值较低,对应激致病因子的反应更敏感.当应对免疫原刺激引起防御反应时可诱发代谢重塑的适应性反应.如果过度反应即引起代谢异常,后者反馈引起免疫系统重塑,称为免疫代谢.近年来,本课题组连续报道了HHcy通过引起细胞缺氧和代谢应激,分别诱导高代谢率的T淋巴细胞、B淋巴细胞、巨噬细胞、脂肪细胞以及血小板等的代谢重塑,显著增加膜磷脂的分解和脂质代谢产物蓄积,特别是膜磷脂分解为致炎活性的溶血磷脂酰胆碱和其下游多不饱和脂肪酸对膜磷脂的氧化和糖基化修饰增加,最终加速脂肪组织慢性炎症和动脉粥样硬化及其并发症的发生.另一方面这些细胞通过增加线粒体β氧化或脂肪产热,均可明显减少Hcy和高脂引起的上述病变.应用膜磷脂分解抑制剂、AMPK激酶激动剂或过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptors,PPARα)的激动剂均明显改善免疫代谢和血管慢性炎症.因此,改善免疫代谢是早期预防和治疗代谢性心血管疾病的重要新策略.

Hyperhomocysteinemia(HHcy),which is caused by genetic defects on methionine metabolism or metabolic defects on transsulfurization pathways,is an independent risk factor for cardiovascular diseases.Immune cells are highly dependent on oxidative metabolism,and their mitochondrial pathogenic mutation threshold is low;therefore,immune cells are more sensitive to multiple stresses.Adaptive responses of metabolic remodeling will be induced when immune cells are under stimulation with immunogenic stimuli.While these responses are overwhelming,abnormally metabolic status will be induced and the immune system will be reshaped.This process is called“immunometabolism”.In recent years,our group has continuously reported that HHcy induces metabolic remodeling of T lymphocytes,B lymphocytes,macrophages,adipocytes and platelets with high metabolic rate by causing cellular hypoxia and metabolic stress.HHcy significantly increases the decomposition of membrane phospholipids into proinflammatory lysophosphatidylcholine and polyunsaturated fatty acids.HHcy also increases the oxidation or glycosylation modification of membrane phospholipids,which ultimately accelerates the chronic inflammation in adipose tissues and blood vessels.On the other hand,these cells can also significantly reduce the above-mentioned pathological changes by increasing mitochondrialβoxidation or thermogenesis.The membrane phospholipid decomposition inhibitors,AMPK kinase agonists or peroxisome proliferator activated receptor alpha(PPARα)agonists can significantly alleviate immunometabolism and chronic vascular inflammation.Therefore,targeting immunometabolism is an important strategy for early prevention and treatment of metabolic cardiovascular diseases.