Department of Physiology, University of Melbourne, Melbourne, VIC, Australia.
J Mol Cell Cardiol. 2011 Jun;50(6):1035-43. doi: 10.1016/j.yjmcc.2011.03.002. Epub 2011 Mar 6.
Fructose intake is linked with the increasing prevalence of insulin resistance and there is now evidence for a specific insulin-resistant cardiomyopathy. The aim of this study was to determine the cardiac-specific myocardial remodeling effects of high fructose dietary intake. Given the links between insulin signaling, reactive oxygen species generation and autophagy induction, we hypothesized that autophagy contributes to pathologic remodeling in the insulin-resistant heart, and in particular may be a feature of high fructose diet-induced cardiac phenotype. Male C57Bl/6 mice were fed a high fructose (60%) diet or nutrient-matched control diet for 12 weeks. Systemic and myocardial insulin-resistant status was characterized. Superoxide production (lucigenin) and cellular growth and death signaling pathways were examined in myocardial tissue. Myocardial structural remodeling was evaluated by measurement of heart weight indices and histological analysis of collagen deposition (picrosirius red). Fructose-fed mice exhibited hyperglycemia and glucose intolerance, but plasma insulin and blood pressure were unchanged. High fructose intake suppressed the myocardial Akt cell survival signaling coincident with increased cardiac superoxide generation (21% increase, p<0.05). Fructose feeding induced elevated autophagy (LC3B-II: LC3B-I ratio: 46% increase, p<0.05) but not apoptosis signaling (unchanged Bax-1:Bcl-2 ratio). Despite a 28% increase in interstitial fibrosis, no difference in heart weight was observed in fructose-fed mice. We provide the first evidence that myocardial autophagy activation is associated with systemic insulin resistance, and that high level fructose intake inflicts direct cardiac damage. Upregulated autophagy is associated with elevated cardiac superoxide production, suppressed cell survival signaling and fibrotic infiltration in fructose-fed mice. The novel finding that autophagy contributes to cardiac pathology in insulin resistance identifies a new therapeutic target for diabetic cardiomyopathy.
果糖摄入与胰岛素抵抗的患病率增加有关，现在有证据表明存在特定的胰岛素抵抗性心肌病。本研究旨在确定高果糖饮食摄入对心脏特异性心肌重构的影响。鉴于胰岛素信号转导、活性氧生成和自噬诱导之间的联系，我们假设自噬有助于胰岛素抵抗心脏的病理性重构，特别是可能是高果糖饮食诱导的心脏表型的特征。雄性 C57Bl/6 小鼠喂食高果糖（60%）饮食或营养匹配的对照饮食 12 周。 描述了系统性和心肌胰岛素抵抗状态。 检测心肌组织中超氧阴离子的产生（荧光素）和细胞生长和死亡信号通路。 通过测量心脏重量指数和胶原沉积（苦味酸天狼猩红）的组织学分析来评估心肌结构重构。 果糖喂养的小鼠表现出高血糖和葡萄糖不耐受，但血浆胰岛素和血压不变。 高果糖摄入抑制了心肌 Akt 细胞存活信号，同时增加了心脏超氧阴离子的产生（增加 21%，p<0.05）。 果糖喂养诱导了升高的自噬（LC3B-II：LC3B-I 比值：增加 46%，p<0.05），但没有诱导凋亡信号（Bax-1：Bcl-2 比值不变）。 尽管间质纤维化增加了 28%，但在果糖喂养的小鼠中没有观察到心脏重量的差异。 我们提供了第一个证据表明心肌自噬激活与系统性胰岛素抵抗有关，并且高水平果糖摄入会对心脏造成直接损伤。 在果糖喂养的小鼠中，上调的自噬与升高的心脏超氧阴离子产生、抑制细胞存活信号和纤维化浸润有关。 自噬有助于胰岛素抵抗性心肌病的心脏病理学的新发现为糖尿病性心肌病确定了一个新的治疗靶点。
