Oudit Gavin Y, Sun Hui, Trivieri Maria G, Koch Sheryl E, Dawood Fayez, Ackerley Cameron, Yazdanpanah Mehrdad, Wilson Greg J, Schwartz Arnold, Liu Peter P, Backx Peter H
Heart and Stroke/Richard Lewar Centre of Excellence, Departments of Medicine and Physiology, University of Toronto, Ontario M5S 3E2, Canada.
Nat Med. 2003 Sep;9(9):1187-94. doi: 10.1038/nm920. Epub 2003 Aug 24.
Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.
在铁过载的情况下，这种情况目前在全球范围内正达到流行程度，铁过载性心肌病是影响患者生存的最重要预后因素。我们推测，在铁过载疾病中，心脏中的铁积累取决于亚铁离子（Fe2+）通过L型电压依赖性钙通道（LVDCC）的渗透，LVDCC是一种混杂的二价阳离子转运体。小鼠铁过载与死亡率增加、收缩和舒张功能障碍、心动过缓、低血压、心肌纤维化增加以及氧化应激升高有关。使用治疗剂量的LVDCC阻滞剂（CCB；氨氯地平和维拉帕米）进行治疗可抑制心肌细胞中的LVDCC电流，减轻心肌铁积累和氧化应激，提高生存率，预防低血压，并维持心脏结构和功能。与LVDCC在心肌铁摄取中的作用一致，与同窝对照相比，心脏特异性过表达LVDCCα1亚基的铁过载转基因小鼠的心肌铁和氧化应激水平高出两倍，心脏功能损害也更大；LVDCC阻断再次具有保护作用。我们的结果表明，在铁过载条件下，心脏LVDCC是铁进入心肌细胞的关键转运体，并且可能代表一个新的治疗靶点，以减轻铁过载带来的心血管负担。
