Prosser Hamish C G, Forster Malcolm E, Richards A Mark, Pemberton Chris J
School of Biological Sciences, University of Canterbury, PO Box 4800, Christchurch, New Zealand.
Cardiovasc Res. 2009 Apr 1;82(1):40-50. doi: 10.1093/cvr/cvp003. Epub 2009 Jan 15.
The aim of this study was to observe the direct physiological and biochemical cardiac effects in response to a newly identified putative component of the renin-angiotensin system, proangiotensin-12 (PA12); and investigate whether PA12 can serve as a substrate for Angiotensin II (AngII) generation.
The direct cardiac actions of PA12 and its role as a substrate for chymase-dependent AngII generation were investigated in Sprague-Dawley rats using an isolated heart model of cardiac ischaemia-reperfusion injury. PA12 potently constricted coronary arteries with no significant effect on left-ventricular contractility. PA12 impaired recovery from global ischaemia, maintaining coronary constriction and markedly increasing release of creatine kinase and troponin I (TnI), indicating greater myocardial injury. Analysis of perfusate collected after transcardiac passage revealed a marked increase in AngII production from hearts infused with PA12. Cardiac AngII production was not blocked by angiotensin-converting enzyme inhibitors, whereas inhibition of chymase with chymostatin significantly reduced AngII production and attenuated PA12-induced vasoconstriction and myocardial damage following ischaemia. Furthermore, Angiotensin II type 1 receptor (AT(1)R) blockade abolished PA12 activity. In vitro, PA12 was efficiently and precisely converted to AngII as assessed on reverse phase-high performance liquid chromatography coupled to tandem mass spectrometry. This conversion was blocked by chymostatin.
PA12 may act as a circulating substrate for cardiac chymase-mediated AngII production, in contrast to ACE-mediated AngII production from AngI.
本研究旨在观察一种新发现的肾素 - 血管紧张素系统假定成分——血管紧张素原 -12（PA12）对心脏的直接生理生化影响；并研究PA12是否可作为生成血管紧张素II（AngII）的底物。
使用心脏缺血 - 再灌注损伤的离体心脏模型，在Sprague - Dawley大鼠中研究了PA12的直接心脏作用及其作为糜酶依赖性AngII生成底物的作用。PA12能强烈收缩冠状动脉，对左心室收缩性无显著影响。PA12损害了整体缺血后的恢复，维持冠状动脉收缩，并显著增加肌酸激酶和肌钙蛋白I（TnI）的释放，表明心肌损伤更严重。对经心脏灌注后收集的灌注液分析显示，灌注PA12的心脏中AngII生成显著增加。血管紧张素转换酶抑制剂未阻断心脏AngII的生成，而用抑肽酶抑制糜酶可显著降低AngII生成，并减轻缺血后PA12诱导的血管收缩和心肌损伤。此外，1型血管紧张素II受体（AT(1)R）阻断消除了PA12的活性。在体外，通过反相高效液相色谱 - 串联质谱评估，PA12能有效且精确地转化为AngII。这种转化被抑肽酶阻断。
与血管紧张素I经血管紧张素转换酶介导生成AngII不同，PA12可能作为心脏糜酶介导的AngII生成的循环底物。
