Das Subhash K, Patel Vaibhav B, Basu Ratnadeep, Wang Wang, DesAulniers Jessica, Kassiri Zamaneh, Oudit Gavin Y
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
J Am Heart Assoc. 2017 Jan 23;6(1):e003456. doi: 10.1161/JAHA.116.003456.
Sex-related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron-overload cardiomyopathy is poorly understood.
Male and female wild-type and hemojuvelin-null mice were injected and fed with a high-iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron-overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron-overloaded mice based on echocardiographic and invasive pressure-volume analyses. Female mice demonstrated a marked suppression of iron-mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron-overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron-induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17β-Estradiol therapy rescued the iron-overload cardiomyopathy in male wild-type mice. The responses in wild-type and hemojuvelin-null female mice were remarkably similar, highlighting a conserved mechanism of sex-dependent protection from iron-overload-mediated cardiac injury.
Male and female mice respond differently to iron-overload-mediated effects on heart structure and function, and females are markedly protected from iron-overload cardiomyopathy. Ovariectomy in female mice exacerbated iron-induced myocardial injury and precipitated severe cardiac dysfunction during iron-overload conditions, whereas 17β-estradiol therapy was protective in male iron-overloaded mice.
在人类和实验动物中，心脏功能和铁代谢存在性别差异。男性患者和临床前动物模型更容易患心肌病和心力衰竭。然而，在铁过载性心肌病中是否存在类似差异尚不清楚。
分别对雄性和雌性野生型及遗传性血色素沉着症小鼠注射并给予高铁饮食，以诱导继发性铁过载和遗传性血色素沉着症。雌性小鼠完全免受铁过载性心肌病的影响，而基于超声心动图和有创压力-容积分析，铁过载导致雄性铁过载小鼠出现明显的舒张功能障碍。尽管心肌铁沉积程度相当，但雌性小鼠铁介导的氧化应激受到显著抑制，且无心肌纤维化。去卵巢的铁过载雌性小鼠表现出铁过载性心肌病的基本病理生理特征，包括明显的舒张和收缩功能障碍、严重的心肌纤维化、心肌氧化应激增加以及心脏病标志物表达增加。去卵巢阻止了铁诱导铁蛋白的上调，降低了心肌肌浆网钙ATP酶2a水平，并增加了钠钙交换体1水平。17β-雌二醇治疗可挽救雄性野生型小鼠的铁过载性心肌病。野生型和遗传性血色素沉着症雌性小鼠的反应非常相似，但突出了性别依赖性保护免受铁过载介导的心脏损伤的保守机制。
雄性和雌性小鼠对铁过载介导的心脏结构和功能影响反应不同，雌性明显免受铁过载性心肌病的影响。雌性小鼠去卵巢加剧了铁诱导的心肌损伤，并在铁过载条件下引发严重的心脏功能障碍，而17β-雌二醇治疗对雄性铁过载小鼠具有保护作用。
