Dutta Debapriya, Xu Jinze, Dirain Marvin L S, Leeuwenburgh Christiaan
Department of Aging and Geriatric Research, Institute on Aging, and University of Florida, Gainesville, FL 32610, USA.
Department of Aging and Geriatric Research, Institute on Aging, and University of Florida, Gainesville, FL 32610, USA; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA.
Free Radic Biol Med. 2014 Sep;74:252-62. doi: 10.1016/j.freeradbiomed.2014.06.011. Epub 2014 Jun 26.
The multiple beneficial effects of calorie restriction (CR) on several organs, including the heart, are widely known. Recently, the plant polyphenol resveratrol has been shown to possess several beneficial effects similar to those of CR. Among the host of effects on cardiac muscle, a cellular self-eating process called autophagy has been shown to be induced by both CR and resveratrol. Autophagy is vital in removing dysfunctional organelles and damaged proteins from the cell, thereby maintaining cellular quality control. In this study, we explored whether short-term moderate CR (20%), either alone or in combination with resveratrol, can induce autophagy in the hearts of 26-month-old Fischer 344 × Brown Norway rats. Autophagy stimulation was investigated by measuring the protein expression levels of the autophagy proteins beclin-1, Atg5, and p62 and the LC3-II/LC3-I ratio. We found that 20% CR or resveratrol alone for 6 weeks could not induce autophagy, but 20% CR in combination with 50 mg/kg/day resveratrol resulted in an induction of autophagy in the hearts of 26-month-old rats. Although oxidative stress has been proposed to be an inducer of autophagy, treatment with the chemotherapeutic drug doxorubicin was unable to stimulate autophagy. The enhanced autophagy due to CR + resveratrol was associated with protection from doxorubicin-induced damage, as measured by cardiac apoptotic levels and serum creatine kinase and lactate dehydrogenase activity. We propose that a combinatorial approach of low-dose CR and resveratrol has the potential to be used therapeutically to induce autophagy and provides protection against doxorubicin-mediated toxicity.
热量限制（CR）对包括心脏在内的多个器官具有多种有益作用，这是广为人知的。最近，植物多酚白藜芦醇已被证明具有与CR相似的多种有益作用。在对心肌的一系列作用中，一种称为自噬的细胞自我吞噬过程已被证明可由CR和白藜芦醇诱导。自噬对于从细胞中清除功能失调的细胞器和受损蛋白质至关重要，从而维持细胞质量控制。在本研究中，我们探讨了短期适度热量限制（20%）单独或与白藜芦醇联合使用是否能在26月龄的Fischer 344×Brown Norway大鼠心脏中诱导自噬。通过测量自噬蛋白beclin-1、Atg5和p62的蛋白表达水平以及LC3-II/LC3-I比率来研究自噬刺激情况。我们发现，单独进行6周的20%热量限制或使用白藜芦醇均不能诱导自噬，但20%热量限制与50mg/kg/天白藜芦醇联合使用可在26月龄大鼠心脏中诱导自噬。尽管氧化应激被认为是自噬的诱导剂，但使用化疗药物阿霉素进行治疗无法刺激自噬。通过心脏凋亡水平以及血清肌酸激酶和乳酸脱氢酶活性测量发现，CR + 白藜芦醇导致的自噬增强与对阿霉素诱导损伤的保护作用相关。我们提出，低剂量CR和白藜芦醇的联合方法有可能用于治疗性诱导自噬，并提供针对阿霉素介导毒性的保护作用。
