Rhoden Alexandra, Friedrich Felix W, Brandt Theresa, Raabe Janice, Schweizer Michaela, Meisterknecht Jana, Wittig Ilka, Ulmer Bärbel M, Klampe Birgit, Uebeler June, Piasecki Angelika, Lorenz Kristina, Eschenhagen Thomas, Hansen Arne, Cuello Friederike
Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Redox Biol. 2021 May;41:101951. doi: 10.1016/j.redox.2021.101951. Epub 2021 Mar 31.
Sulforaphane (SFN) is a phytochemical compound extracted from cruciferous plants, like broccoli or cauliflower. Its isothiocyanate group renders SFN reactive, thus allowing post-translational modification of cellular proteins to regulate their function with the potential for biological and therapeutic actions. SFN and stabilized variants recently received regulatory approval for clinical studies in humans for the treatment of neurological disorders and cancer. Potential unwanted side effects of SFN on heart function have not been investigated yet. The present study characterizes the impact of SFN on cardiomyocyte contractile function in cardiac preparations from neonatal rat, adult mouse and human induced-pluripotent stem cell-derived cardiomyocytes. This revealed a SFN-mediated negative inotropic effect, when administered either acutely or chronically, with an impairment of the Frank-Starling response to stretch activation. A direct effect of SFN on myofilament function was excluded in chemically permeabilized mouse trabeculae. However, SFN pretreatment increased lactate formation and enhanced the mitochondrial production of reactive oxygen species accompanied by a significant reduction in the mitochondrial membrane potential. Transmission electron microscopy revealed disturbed sarcomeric organization and inflated mitochondria with whorled membrane shape in response to SFN exposure. Interestingly, administration of the alternative energy source l-glutamine to the medium that bypasses the uptake route of pyruvate into the mitochondrial tricarboxylic acid cycle improved force development in SFN-treated EHTs, suggesting indeed mitochondrial dysfunction as a contributor of SFN-mediated contractile dysfunction. Taken together, the data from the present study suggest that SFN might impact negatively on cardiac contractility in patients with cardiovascular co-morbidities undergoing SFN supplementation therapy. Therefore, cardiac function should be monitored regularly to avoid the onset of cardiotoxic side effects.
萝卜硫素（SFN）是一种从十字花科植物（如西兰花或花椰菜）中提取的植物化学化合物。其异硫氰酸酯基团使SFN具有反应活性，从而允许对细胞蛋白质进行翻译后修饰，以调节其功能，具有生物学和治疗作用的潜力。SFN及其稳定变体最近获得监管批准，可用于人类治疗神经疾病和癌症的临床研究。SFN对心脏功能潜在的不良副作用尚未得到研究。本研究描述了SFN对新生大鼠、成年小鼠和人诱导多能干细胞衍生心肌细胞心脏制剂中心肌细胞收缩功能的影响。这揭示了急性或慢性给予SFN时，其介导的负性肌力作用，以及对牵张激活的Frank-Starling反应受损。在化学通透的小鼠小梁中排除了SFN对肌丝功能的直接作用。然而，SFN预处理增加了乳酸生成，并增强了线粒体活性氧的产生，同时线粒体膜电位显著降低。透射电子显微镜显示，暴露于SFN后，肌节组织紊乱，线粒体肿胀，膜呈螺旋状。有趣的是，向培养基中添加替代能源L-谷氨酰胺，绕过丙酮酸进入线粒体三羧酸循环的摄取途径，改善了SFN处理的EHTs中的力发展，这表明线粒体功能障碍确实是SFN介导的收缩功能障碍的一个原因。综上所述，本研究的数据表明，在接受SFN补充治疗的心血管合并症患者中，SFN可能对心脏收缩力产生负面影响。因此，应定期监测心脏功能，以避免心脏毒性副作用的发生。
