Raju V S, Maines M D
University of Rochester School of Medicine, Department of Biophysics, Environmental Medicine, New York, USA.
J Pharmacol Exp Ther. 1996 Jun;277(3):1814-22.
For the first time, the authors report an intimate link between kidney and heart functions as it pertains to the regulation of stress protein gene expression in the heart. They show that the stress on the target organ, the kidney, is translated into a response in the cardiovascular system, as reflected by the induction of heme oxygenase (HO)-1 gene expression, which, in turn, may be a cellular defense response as suggested by an increase in cGMP level in the heart, and an increase in the rate of bilirubin formation by the kidney and the heart. HO-1 is a stress protein (HSP32) and, together with HO-2, catalyzes oxidation of the heme molecule to generate CO, a likely signal molecule for the generation of cGMP, and bilirubin, an antioxidant. Specifically, bilateral renal ischemia for 30 min caused a 3-fold increase in the approximately 1.8-kb HO-1 mRNA in the heart within 4 h after reperfusion and remained essentially at this level for 24 h, at which point, a 2.6-fold increase in HO-1 mRNA in the descending aorta was also detected. Heart HO-1 mRNA remained elevated for more than 48 h; in contrast, at the 48-h time point, the transcript level in the kidney, which had increased by 10-fold 24 h after reperfusion, had returned to the control level. Neither in the heart nor in the kidney did HO-2 transcripts (approximately 1.3 and 1.9 kb) respond to renal ischemia/ reperfusion. The increase in heart HO-1 transcript level was accompanied by an increase in HO-1 protein, as judged by Western blot and immunohistochemical analysis, and in enzyme activity, as judged by bilirubin formation. In addition, cGMP concentration in the heart was elevated when measured at 24 h and 48 h after reperfusion of the kidney, in the absence of an increase in the activity of NO. Data suggest that hemodynamic stress caused by the occlusion of the renal artery is responsible for activation of HO-1 gene expression in the heart. An argument is made for the role of HO-1 in the defense mechanisms of the heart pertaining to the enzyme's function in a hemoprotein regulatory capacity, along with the biological activity of its products.
作者首次报告了肾脏与心脏功能之间的密切联系，这种联系与心脏应激蛋白基因表达的调控有关。他们表明，靶器官肾脏所受的应激转化为心血管系统的一种反应，这表现为血红素加氧酶（HO）-1基因表达的诱导，而这反过来可能是一种细胞防御反应，证据是心脏中cGMP水平升高，以及肾脏和心脏中胆红素生成速率增加。HO-1是一种应激蛋白（HSP32），它与HO-2一起催化血红素分子氧化，生成CO（一种可能是生成cGMP的信号分子）和胆红素（一种抗氧化剂）。具体而言，双侧肾脏缺血30分钟后，再灌注4小时内心脏中约1.8kb的HO-1 mRNA增加了3倍，并在24小时内基本维持在这一水平，此时降主动脉中HO-1 mRNA也增加了2.6倍。心脏HO-1 mRNA在48小时以上保持升高；相比之下，在48小时时间点，肾脏中再灌注24小时后增加了10倍的转录水平已恢复到对照水平。HO-2转录本（约1.3kb和1.9kb）在心脏和肾脏中均未对肾脏缺血/再灌注产生反应。通过蛋白质免疫印迹和免疫组织化学分析判断，心脏HO-1转录水平的增加伴随着HO-1蛋白的增加，通过胆红素生成判断，酶活性也增加。此外，在肾脏再灌注后24小时和48小时测量时，心脏中的cGMP浓度升高，而一氧化氮（NO）活性并未增加。数据表明，肾动脉阻塞引起的血流动力学应激是心脏中HO-1基因表达激活的原因。有人认为HO-1在心脏的防御机制中发挥作用，这与其在血红素蛋白调节能力方面的功能及其产物的生物活性有关。
