Leibetseder Valentin, Humpeler Susanne, Svoboda Martin, Schmid Diethart, Thalhammer Theresia, Zuckermann Andreas, Marktl Wolfgang, Ekmekcioglu Cem
Center of Physiology and Pharmacology, University Vienna, Austria.
Chronobiol Int. 2009 May;26(4):621-36. doi: 10.1080/07420520902924939.
Thus far, clock genes in the heart have been described only in rodents, and alterations of these genes have been associated with various myocardial malfunctions. In this study, we analyzed the expression of clock genes in human hearts. Left papillary muscles of 16 patients with coronary heart disease, 39 subjects with cardiomyopathy, and 9 healthy donors (52 males and 12 females, mean age 55.7+/-11.2; 16-70 yrs) were obtained during orthotopic heart transplantation. We assessed the mRNA levels of PER1, PER2, BMAL1, and CRY1 by real time PCR and analyzed their rhythmic expression by sliding means and Cosinor functions. Furthermore, we sought for differences between the three groups (by ANOVAs) for both the total 24 h period and separate time bins. All four clock genes were expressed in human hearts. The acrophases (circadian rhythm peak time) of the PER mRNAs occurred in the morning (PER1: 07:44 h [peak level 187% higher than trough, p = .008]; PER2: 09:42 h [peak 254% higher than trough, p < .0001], and BMAL1 mRNA in the evening at 21:44 h [peak 438% higher than trough; p < .0001]. No differences were found in the rhythmic patterns between the three groups. No circadian rhythm was detected in CRY1 mRNA in any group. PER1, PER2, and BMAL1 mRNAs revealed clear circadian rhythms in the human heart, with their staging being in antiphase to those in rodents. The circadian amplitudes of the mRNA clock gene levels in heart tissue are more distinct than in any other human tissue so far investigated. The acrophase of the myocardial PER mRNAs and the trough of the myocardial BMAL1 coincide to the time of day of most frequent myocardial incidents.
迄今为止，心脏中的生物钟基因仅在啮齿动物中被描述过，这些基因的改变与各种心肌功能障碍有关。在本研究中，我们分析了生物钟基因在人类心脏中的表达。在原位心脏移植过程中获取了16例冠心病患者、39例心肌病患者以及9名健康供体（52名男性和12名女性，平均年龄55.7±11.2岁；16 - 70岁）的左乳头肌。我们通过实时PCR评估了PER1、PER2、BMAL1和CRY1的mRNA水平，并通过滑动均值和余弦分析函数分析了它们的节律性表达。此外，我们通过方差分析寻找三组在整个24小时期间以及各个时间段的差异。所有四个生物钟基因均在人类心脏中表达。PER mRNA的峰值相位（昼夜节律峰值时间）出现在上午（PER1：07:44 h [峰值水平比谷值高187%，p = 0.008]；PER2：09:42 h [峰值比谷值高254%，p < 0.0001]），而BMAL1 mRNA的峰值相位出现在晚上21:44 h [峰值比谷值高438%；p < 0.0001]。三组之间的节律模式未发现差异。在任何组中均未检测到CRY1 mRNA的昼夜节律。PER1、PER2和BMAL1 mRNA在人类心脏中显示出明显的昼夜节律，其相位与啮齿动物中的相反。心脏组织中mRNA生物钟基因水平的昼夜振幅比迄今为止研究的任何其他人体组织都更明显。心肌PER mRNA的峰值相位和心肌BMAL1的谷值相位与最频繁发生心肌事件的一天中的时间一致。
