Lodwick D, Kaiser M A, Harris J, Cumin F, Vincent M, Samani N J
Department of Medicine, University of Leicester, Leicester Royal Infirmary, UK.
Hypertension. 1995 Jun;25(6):1245-51. doi: 10.1161/01.hyp.25.6.1245.
Allelic variants at the human angiotensinogen locus have recently been reported to increase susceptibility to the development of essential hypertension. In this study we analyzed the role played by angiotensinogen in the elevated blood pressure of the spontaneously hypertensive rat (SHR). The SHR angiotensinogen locus (on chromosome 19) cosegregated with a significant (P = .003) and specific increase in pulse pressure in F2 rats derived from a cross of the SHR with the normotensive Wistar-Kyoto rat (WKY), accounting for 20% of the genetic (10% of total) variance in this phenotype. To identify potential mechanisms underlying the effect of the locus, we further examined angiotensinogen structure and expression in the two strains. Sequence analysis of the respective coding regions revealed no differences in the primary structure of angiotensinogen between the strains. Likewise, plasma angiotensinogen level did not differ in adult rats of the two strains. However, gene expression studies showed tissue-specific, age-related differences in angiotensinogen mRNA levels between SHR and WKY, particularly in the aorta. The findings suggest that pulse pressure, which significantly influences cardiovascular risk, has independent genetic determinants. They further suggest that the effect of the angiotensinogen locus on this phenotype in the SHR may be mediated through a tissue-specific abnormality of angiotensinogen gene expression.
最近有报道称，人类血管紧张素原基因座上的等位基因变异会增加患原发性高血压的易感性。在本研究中，我们分析了血管紧张素原在自发性高血压大鼠（SHR）血压升高中所起的作用。SHR的血管紧张素原基因座（位于第19号染色体上）与来自SHR与正常血压的Wistar-Kyoto大鼠（WKY）杂交的F2代大鼠脉压显著（P = 0.003）且特异性升高共分离，占该表型遗传变异（占总变异的10%）的20%。为了确定该基因座作用的潜在机制，我们进一步研究了这两个品系中血管紧张素原的结构和表达。对各自编码区的序列分析显示，两个品系之间血管紧张素原的一级结构没有差异。同样，两个品系成年大鼠的血浆血管紧张素原水平也没有差异。然而，基因表达研究表明，SHR和WKY之间血管紧张素原mRNA水平存在组织特异性、与年龄相关的差异，特别是在主动脉中。这些发现表明，对心血管风险有显著影响的脉压有独立的遗传决定因素。它们还进一步表明，血管紧张素原基因座对SHR这一表型的影响可能是通过血管紧张素原基因表达的组织特异性异常介导的。
