Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy.
Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy.
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作者：
Rajesh M;Bátkai S;Kechrid M;Mukhopadhyay P;Lee WS;Horváth B;Holovac E;Cinar R;Liaudet L;Mackie K;Haskó G;Pacher P
内源性大麻素和大麻素1（CB 1）受体与心脏功能障碍、炎症和与各种形式的休克、心力衰竭和动脉粥样硬化相关的细胞死亡有关，此外，它们在肥胖/代谢综合征和糖尿病中的各种心血管危险因素的发展中也有公认的作用。在这项研究中，我们探讨了CB 1受体在心肌功能障碍，炎症，氧化/硝化应激，细胞死亡和相关的信号通路中的作用，使用1型糖尿病心肌病小鼠模型。糖尿病性心肌病的特征是心肌内源性大麻素anandamide水平升高，氧化/硝化应激，p38/Jun NH 2-末端激酶（JNK）丝裂原活化蛋白激酶（MAPK）激活，炎症反应增强，（肿瘤坏死因子-α、白细胞介素-1 β、环氧合酶2、细胞内粘附分子1和血管细胞粘附分子1），CB 1表达增加，晚期糖基化终产物（AGE）和血管紧张素II 1型受体（晚期糖基化终产物受体[ARG]，血管紧张素II受体1型[AT 1 R]），p47（phox）NADPH氧化酶亚基，β-肌球蛋白重链同工酶转换，AGE蓄积，纤维化，肌质/内质网Ca ~（2+）-ATP酶（SERCA 2a）表达降低。药物抑制或基因缺失CB 1受体可减轻糖尿病引起的心功能不全及上述病理改变。内源性大麻素激活CB 1受体可能通过促进MAPK激活、AT 1 R表达/信号传导、AGE积累、氧化/硝化应激、炎症和纤维化在糖尿病性心肌病的发病机制中发挥重要作用。相反，CB 1受体抑制可能有利于治疗糖尿病心血管并发症。
Endocannabinoids and cannabinoid 1 (CB1) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB1 receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH2-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB1, advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT1R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB1 receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT1R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.
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影响因子：
7.7
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