Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase
Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase
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DOI：
10.1152/ajpheart.00373.2007
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发表时间：
2007-08-01
影响因子：
4.8
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
作者：
Batkai, Sandor;Rajesh, Mohanraj;Pacher, Pal
在缺乏脂肪酸酰胺水解酶的小鼠中，减少与年龄相关的心功能障碍、心肌硝化应激、炎症基因表达和细胞凋亡。[J] .中华心脏杂志，2009,31(3):393 - 398。首次发表于2007年4月13日；doi: 10.1152 / ajpheart.00373.2007。最近的研究发现，炎症、活性氧和活性氮的产生以及脂质代谢在心血管衰老的发病机制中起着重要的交互作用。抑制内源性大麻素anandamide代谢酶，脂肪酸酰胺水解酶（FAAH），正在成为治疗各种炎症性疾病的一种有前途的新方法。在这项研究中，我们研究了FAAH敲除（FAAH(-/-)）小鼠及其野生型（FAAH(+/+)）幼崽中与年龄相关的心功能下降、炎症基因表达、营养应激和细胞凋亡的变化。此外，我们还探讨了anandamide对tnf α诱导的人冠状动脉内皮细胞（HCAECs）中ICAM-1和VCAM-1表达和单核细胞内皮粘附的影响。2- 3龄（年轻）FAAH（-/-）和FAAH（+/+）小鼠的心功能（通过压力-容量传导导管系统测量）没有差异。相比之下，在28- 31岁（衰老）FAAH（+/+）小鼠中观察到的与衰老相关的心功能下降和心肌基因tnf - α、gp91phox、基质金属蛋白酶(MMP)-2、MMP-9、caspase-3和caspase-9表达增加，心肌诱导型一氧化氮合酶蛋白表达，硝基酪氨酸形成，聚（adp核糖）聚合酶裂解和caspase3/9活性，在敲除中大部分减弱。年轻和衰老FAAH（-/-）和FAAH（+/+）小鼠心肌大麻素CB1和CB2受体基因表达无差异。Anandamide以CB1和cb2依赖的方式，剂量依赖性地减弱tnf - α诱导的ICAM-1和VCAM-1表达、NF-kappa B激活以及单核细胞与hcaec的粘附。这些研究结果表明，FAAH的药理抑制可能代表了一种新的保护策略，可以对抗与心血管衰老和动脉粥样硬化相关的慢性炎症、氧化/硝化应激和细胞凋亡。
Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol 293: H909 - H918, 2007. First published April 13, 2007; doi:10.1152/ajpheart.00373.2007. - Recent studies have uncovered important cross talk between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of cardiovascular aging. Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase ( FAAH), is emerging as a promising novel approach for the treatment of various inflammatory disorders. In this study, we have investigated the age-associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout ( FAAH(-/-)) mice and their wild-type (FAAH(+/+)) littermates. Additionally, we have explored the effects of anandamide on TNF-alpha-induced ICAM-1 and VCAM-1 expression and monocyte-endothelial adhesion in human coronary artery endothelial cells (HCAECs). There was no difference in the cardiac function (measured by the pressure-volume conductance catheter system) between 2- to 3-mo-old (young) FAAH(-/-) and FAAH(+/+) mice. In contrast, the aging-associated decline in cardiac function and increased myocardial gene expression of TNF-alpha, gp91phox, matrix metalloproteinase (MMP)-2, MMP-9, caspase-3 and caspase-9, myocardial inducible nitric oxide synthase protein expression, nitrotyrosine formation, poly (ADP-ribose) polymerase cleavage and caspase3/9 activity, observed in 28- to 31-mo-old (aging) FAAH(+/+) mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB1 and CB2 receptor gene expression between young and aging FAAH(-/-) and FAAH(+/+) mice. Anandamide dose dependently attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression, NF-kappa B activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB1 and CB2-dependent manner. These findings suggest that pharmacological inhibition of FAAH may represent a novel protective strategy against chronic inflammation, oxidative/nitrative stress, and apoptosis associated with cardiovascular aging and atherosclerosis.