The Journal of Nutritional Biochemistry ( IF 5.6 ) Pub Date : 2021-06-06 , DOI: 10.1016/j.jnutbio.2021.108798 Salma M Eraky 1 , Nehal M Ramadan 2
Diabetic cardiomyopathy is a primary cause of increased morbidity and mortality in diabetics. Evidence has suggested a pivotal role for interrupted mitochondrial dynamics and quality control machinery in the onset and development of diabetic cardiomyopathy. Sequestosome 1 (SQSTM1) is a major reporter of selective autophagic activity. Other than controlling the expression of genes involved in mitochondrial biogenesis, recently peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) was reported to directly affect SQSTM1 gene expression. Calcineurin, a pivotal mediator of cardiac hypertrophy, has been also linked to enhanced expression of SQSTM1. This study aimed to test the cardioprotective effects of adding ω-3 polyunsaturated fatty acids (PUFAs) to metformin in a rat model of type 2 diabetes mellitus and to evaluate the molecular mechanisms underlying their effects on mitochondrial quality. Diabetes was induced in male Sprague Dawley rats by a high-fat diet for 6 weeks, followed by a low-dose streptozotocin (35 mg/kg). Diabetic rats were either treated with metformin (150 mg/kg/d), ω-3 PUFAs (300 mg/kg/d), or their combination in the same doses for further 8 weeks. Along with metabolic and pathological derangements, we report that correlating with electron microscopic evidence of mitochondrial degeneration, gene expression of the autophagic indicators SQSTM1, PGC-1α, and calcineurin were decreased in the hearts of diabetic rats. Independent of its anti-hyperglycemic effects, metformin successfully preserved mitochondrial integrity and upregulated myocardial PGC-1α, calcineurin, and SQSTM1 gene expression. ω-3 PUFAs possess synergistic cardioprotection when added to metformin, suggested by improvements in myocardial ultrastructure, autophagic activity, and SQSTM1 gene expression.
中文翻译:
omega-3脂肪酸与二甲双胍联合通过自噬途径对大鼠糖尿病心肌病的影响
糖尿病心肌病是糖尿病患者发病率和死亡率增加的主要原因。有证据表明,中断的线粒体动力学和质量控制机制在糖尿病心肌病的发生和发展中起着关键作用。Sequestosome 1 (SQSTM1) 是选择性自噬活动的主要报告者。除了控制参与线粒体生物发生的基因表达外,最近据报道过氧化物酶体增殖物激活受体-γ 共激活因子 1 α (PGC-1α) 直接影响 SQSTM1 基因表达。钙调神经磷酸酶是心脏肥大的关键介质,也与 SQSTM1 的表达增强有关。本研究旨在测试在 2 型糖尿病大鼠模型中向二甲双胍添加 ω-3 多不饱和脂肪酸 (PUFA) 的心脏保护作用,并评估其对线粒体质量影响的分子机制。通过高脂肪饮食在雄性 Sprague Dawley 大鼠中诱导糖尿病 6 周,然后是低剂量链脲佐菌素 (35 mg/kg)。糖尿病大鼠用二甲双胍 (150 mg/kg/d)、ω-3 PUFAs (300 mg/kg/d) 或它们的组合以相同剂量再治疗 8 周。随着代谢和病理紊乱,我们报告称,与线粒体变性的电子显微镜证据相关,糖尿病大鼠心脏中自噬指标 SQSTM1、PGC-1α 和钙调神经磷酸酶的基因表达降低。独立于其抗高血糖作用,二甲双胍成功地保持了线粒体完整性并上调了心肌 PGC-1α、钙调神经磷酸酶和 SQSTM1 基因的表达。当加入二甲双胍时,ω-3 PUFA 具有协同的心脏保护作用,这可以通过改善心肌超微结构、自噬活性和 SQSTM1 基因表达来表明。