The administration of adipose tissue-derived mesenchymal stem cells (ADMSCs) represents a promising therapeutic option after myocardial ischemia or myocardial infarction. However, their potential is reduced due to the high post-transplant cell mortality probably caused by oxidative stress and mitogen-deficient microenvironments. To identify protection strategies for ADMSCs, this study investigated the influence of the non-psychoactive phytocannabinoid cannabidiol (CBD) and the endocannabinoid analogue R(+)-methanandamide (MA) on the induction of heme oxygenase-1 (HO-1) and autophagy under serum-free conditions. At a concentration of 3 µM, CBD induced an upregulation of HO-1 mRNA and protein within 6 h, whereas for MA only a late and comparatively lower increase in the HO-1 protein could be detected after 48 h. In addition, both cannabinoids induced time- and concentration-dependent increases in LC3A/B-II protein, a marker of autophagy, and in metabolic activity. A participation of several cannabinoid-binding receptors in the effect on metabolic activity and HO-1 was excluded. Similarly, knockdown of HO-1 by siRNA or inhibition of HO-1 activity by tin protoporphyrin IX (SnPPIX) had no effect on CBD-induced autophagy and metabolic activity. On the other hand, the inhibition of autophagy by bafilomycin A₁ led to a significant decrease in cannabinoid-induced metabolic activity and to an increase in apoptosis. Under these circumstances, a significant induction of HO-1 expression after 24 h could also be demonstrated for MA. Remarkably, inhibition of HO-1 by SnPPIX under conditions of autophagy deficit led to a significant reversal of apoptosis in cannabinoid-treated cells. In conclusion, the investigated cannabinoids increase metabolic viability of ADMSCs under serum-free conditions by inducing HO-1-independent autophagy but contribute to apoptosis under conditions of additional autophagy deficit via an HO-1-dependent pathway.

中文翻译：

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大麻素诱导的自噬和血红素加氧酶-1确定在压力条件下脂肪组织衍生的间充质干细胞的命运

脂肪组织来源的间充质干细胞（ADMSC）的给药代表了心肌缺血或心肌梗塞后的有希望的治疗选择。但是，由于可能是由氧化应激和促细胞分裂剂缺乏的微环境引起的高移植后细胞死亡率降低了它们的潜力。为了确定ADMSC的保护策略，本研究调查了非精神活性植物大麻素大麻二酚（CBD）和内源性大麻素类似物R（+）-甲酰胺（MA）对血红素加氧酶-1（HO-1）和自噬的诱导作用在无血清条件下。在3 µM的浓度下，CBD会在6 h内诱导HO-1 mRNA和蛋白的上调，而对于MA，在48 h后只能检测到HO-1蛋白的较晚且相对较低的增加。此外，两种大麻素均可诱导时间依赖性和浓度依赖性的LC3A / B-II蛋白（自噬的标志物）和代谢活性的增加。排除了几种大麻素结合受体参与代谢活性和HO-1的作用。同样，通过siRNA抑制HO-1或通过原卟啉IX（SnPPIX）抑制HO-1活性对CBD诱导的自噬和代谢活性没有影响。另一方面，bafilomycin A抑制自噬 siRNA抑制HO-1或锡原卟啉IX（SnPPIX）抑制HO-1活性对CBD诱导的自噬和代谢活性没有影响。另一方面，bafilomycin A抑制自噬 siRNA抑制HO-1或锡原卟啉IX（SnPPIX）抑制HO-1活性对CBD诱导的自噬和代谢活性没有影响。另一方面，bafilomycin A抑制自噬₁导致大麻素诱导的代谢活性显着降低，并导致凋亡增加。在这些情况下，也可以证明MA诱导24小时后HO-1的表达。值得注意的是，在自噬缺陷条件下，SnPPIX对HO-1的抑制作用导致大麻素处理细胞的凋亡发生明显逆转。总之，所研究的大麻素可通过诱导HO-1独立的自噬增加无血清条件下ADMSC的代谢活力，但在通过HO-1依赖的途径在其他自噬不足的条件下促进细胞凋亡。