Selective Regulation of Cardiac Organic Cation Transporter Novel Type 2 (OCTN2) in Dilated Cardiomyopathy
Selective Regulation of Cardiac Organic Cation Transporter Novel Type 2 (OCTN2) in Dilated Cardiomyopathy
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DOI：
10.1016/j.ajpath.2011.02.020
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发表时间：
2011-06-01
影响因子：
6
通讯作者：
Kroemer, Heyo K.
中科院分区：
文献类型：
--
作者：
Grube, Markus;Ameling, Sabine;Kroemer, Heyo K.
有机阳离子转运体（OCT1-3和OCTN1/2）促进内源性化合物和许多药物的心脏摄取。例如，OCTN2的遗传变异会减少对肉碱的吸收，从而导致心力衰竭。OCTs和OCTNs的表达和功能是否会因疾病而改变，目前还没有详细的研究。因此，我们研究了这些转运蛋白的心脏表达、心力衰竭依赖性调节以及对心血管药物的亲和力。心肌转运蛋白mRNA水平为OCTN2>OCT3>OCTN1> OCT1（未检测OCT2）。蛋白定位于血管结构（OCT3/OCTN2/OCTN1）和心肌细胞（OCT1/OCTN1）。功能研究揭示了具有明显OCT1功能抑制的特定药物相互作用谱，例如卡维地洛[一半最大抑制浓度（IC50）， 1.4 μ mol/L]，地尔硫卓（IC50, 1.7 μ mol/L）或普罗帕酮（IC50, 1.0 μ mol/L）。在柯萨奇病毒感染小鼠心肌病模型中，Octn2mRNA表达显著降低（感染后8天为对照组的56%）。因此，在扩张型心肌病患者的心内膜活检标本中，OCTN2的表达明显降低，而OCT1-3和OCTN1的表达不受影响。对于OCTN2，我们观察到表达与左心室射血分数（r = 0.53,P < 0.0001）和心脏CD3(+) T细胞的存在（r = -0.45, P < 0.05）之间存在显著相关性。OCT1、OCT3、OCTN1和OCTN2在人心脏中表达，并与心血管药物相互作用。OCTN2表达在扩张型心肌病患者中选择性降低，并预测心功能损害。（中国病理杂志，2011,178:2547-2559;DOI: 10.1016/ j.j ajpath.2011.02.020）
Organic cation transporters (OCT1-3 and OCTN1/2) facilitate cardiac uptake of endogenous compounds and numerous drugs. Genetic variants of OCTN2, for example, reduce uptake of carnitine, leading to heart failure. Whether expression and function of OCTs and OCTNs are altered by disease has not been explored in detail. We therefore studied cardiac expression, heart failure dependent regulation, and affinity to cardiovascular drugs of these transporters. Cardiac transporter mRNA levels were OCTN2>OCT3>OCTN1> OCT1 (OCT2 was not detected). Proteins were localized in vascular structures (OCT3/OCTN2/OCTN1) and cardiomyocytes (OCT1/OCTN1). Functional studies revealed a specific drug-interaction profile with pronounced inhibition of OCT1 function, for example, carvedilol [half maximal inhibitory concentration (IC50), 1.4 mu mol/L], diltiazem (IC50, 1.7 mu mol/L), or propafenone (IC50, 1.0 mu mol/L). With use of the cardiomyopathy model of coxsackievirus-infected mice, Octn2mRNA expression was significantly reduced (56% of controls, 8 days after infection). Accordingly, in endomyocardial biopsy specimens OCTN2 expression was significantly reduced in patients with dilated cardiomyopathy, whereas the expression of OCT1-3 and OCTN1 was not affected. For OCTN2 we observed a significant correlation between expression and left ventricular ejection fraction (r = 0.53,P < 0.0001) and the presence of cardiac CD3(+) T cells (r = -0.45, P < 0.05), respectively. OCT1, OCT3, OCTN1, and OCTN2 are expressed in the human heart and interact with cardiovascular drugs. OCTN2 expression is selectively reduced in dilated cardiomyopathy patients and predicts the impairment of cardiac function. (Am J Pathol 2011, 178:2547-2559; DOI: 10.1016/j.ajpath.2011.02.020)