Naito Yoshiro, Tsujino Takeshi, Matsumoto Mika, Sakoda Tsuyoshi, Ohyanagi Mitsumasa, Masuyama Tohru
Cardiovascular Division, Dept. of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Am J Physiol Heart Circ Physiol. 2009 Mar;296(3):H585-93. doi: 10.1152/ajpheart.00463.2008. Epub 2009 Jan 9.
Anemia is common in patients with chronic heart failure and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Weanling Sprague-Dawley rats were fed an iron-deficient diet for 20 wk to induce IDA, and the molecular mechanisms of cardiac remodeling were evaluated. The iron-deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and VEGF gene expression increased by 12 wk of IDA, causing angiogenesis in the heart. Thereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression and maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion, with decreased serum Epo concentration and cardiac STAT3 phosphorylation after 20 wk of IDA compared with 12 wk. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with a beneficial adaptive mechanism of anemia-induced cardiac hypertrophy, and later decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long-term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new strategy for treatment of chronic heart failure with anemia.
贫血在慢性心力衰竭患者中很常见，且是预后不良的独立预测因素。慢性贫血会导致左心室肥厚和心力衰竭，但其分子机制仍 largely 未知。我们研究了缺铁性贫血（IDA）诱导的心脏重塑机制，包括分子信号通路。将断乳的 Sprague-Dawley 大鼠喂以缺铁饮食 20 周以诱导 IDA，并评估心脏重塑的分子机制。缺铁饮食最初诱发严重贫血，导致左心室肥厚和扩张，收缩功能保留，同时血清促红细胞生成素（Epo）浓度升高。IDA 持续 12 周时，心脏 STAT3 磷酸化和 VEGF 基因表达增加，导致心脏血管生成。此后，持续的 IDA 诱导心脏缺氧诱导因子-1α基因表达上调，并维持心脏 VEGF 基因表达上调和心脏血管生成；然而，与 12 周相比，持续的 IDA 在 IDA 20 周后促进心脏纤维化和肺充血，血清 Epo 浓度和心脏 STAT3 磷酸化降低。血清 Epo 浓度和心脏 STAT3 磷酸化上调与贫血诱导的心脏肥厚的有益适应性机制相关，而这些分子后期水平降低可能对长期贫血中从适应性心脏肥厚向心脏功能障碍的转变至关重要。了解心脏对贫血适应不良的机制可能会带来治疗伴有贫血的慢性心力衰竭的新策略。
