Gower William R, San Miguel Gloria I, Carter Gay M, Hassan Imran, Farese Robert V, Vesely David L
Department of Biochemistry and Molecular Biology, James A. Haley Veterans Hospital, Tampa, FL 33612, USA.
Mol Cell Biochem. 2003 Oct;252(1-2):263-71. doi: 10.1023/a:1025552029296.
The present investigation was designed to determine if the mechanism for the increased atrial natriuretic peptides within the circulation of diabetic animals involves atrial natriuretic hormone prohormone (proANH) gene expression upregulation. The tissue specificity of this potential upregulation of the proANH gene was investigated in a spontaneous model of type 2 diabetes, i.e. the Goto-Kakizaki (GK) rat with comparison to age-matched non-diabetic Wistar rats from which the GK colony was originally derived. Reverse transcription-polymerase chain reaction revealed that proANH gene expression was increased 3.1-fold in the left heart ventricle, 5-fold in lung, 2-fold in kidney, 3-fold within mucosa and 1.8-fold within muscle of gastric antrum (p < 0.05 for each) of GK rats compared to Wistar rats. There was no significant increase in proANH gene expression in atria and right ventricle of the heart of GK rats compared to Wistars. These results indicate that steady-state ANH prohormone mRNA levels increase within the left ventricle and extracardiac tissues in type 2 diabetic animals. This enhanced gene expression is a functional increase with its expressed proteins (4 peptide hormones; ANPs) increasing 2-6 fold within the circulation of GKs. The greater increase in proANH messenger RNA in the extracardiac tissues compared to the amount of increase within the heart and the greater tissue mass of these combined extra cardiac tissues suggests the majority of the increase in ANPs within the circulation of diabetics is secondary to increased synthesis in extracardiac tissues. This also suggests that there is a systemic regulatory mechanism of proANH gene expression not only within the heart but also within the lung, gastrointestinal tract and kidney. Diabetes is the first disease in which there is more upregulation of ANH prohormone in extracardiac tissues compared to upregulation within the heart itself.
本研究旨在确定糖尿病动物循环中利钠肽增加的机制是否涉及心房利钠激素原激素（proANH）基因表达上调。在2型糖尿病的自发模型即Goto-Kakizaki（GK）大鼠中，研究了proANH基因这种潜在上调的组织特异性，并与最初培育GK大鼠品系的年龄匹配的非糖尿病Wistar大鼠进行比较。逆转录-聚合酶链反应显示，与Wistar大鼠相比，GK大鼠左心室中proANH基因表达增加3.1倍，肺中增加5倍，肾中增加2倍，胃窦黏膜中增加3倍，肌肉中增加1.8倍（各部位p<0.05）。与Wistar大鼠相比，GK大鼠心脏的心房和右心室中proANH基因表达没有显著增加。这些结果表明，2型糖尿病动物的左心室和心外组织中稳态ANH原激素mRNA水平升高。这种增强的基因表达是一种功能性增加，其表达的蛋白质（4种肽激素；ANPs）在GK大鼠循环中增加2至6倍。与心脏内增加的量相比，心外组织中proANH信使RNA增加得更多，并且这些心外组织的组织质量更大，这表明糖尿病患者循环中ANPs增加的大部分是心外组织合成增加的结果。这也表明存在一种proANH基因表达的全身调节机制，不仅存在于心脏内，也存在于肺、胃肠道和肾脏内。糖尿病是第一种与心脏自身上调相比，心外组织中ANH原激素上调更多的疾病。
