Letter by Krop et al Regarding Article, “Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium”
To the Editor:
Angiotensin (Ang) II generation in the heart depends on blood-derived renin and/or prorenin. Both proteins diffuse into the cardiac interstitium or bind to receptors.1 In the case of prorenin, local prorenin–renin conversion is required to allow angiotensin production at cardiac tissue sites. We therefore read with great interest the article by Itoh et al2 in which the authors claim that the diabetic mouse heart contains upregulated levels of a kallikrein-like prorenin-converting enzyme (PRECE). This is of importance because diabetic subjects are known to have increased prorenin levels.1
The authors did not evaluate prorenin activation in the diabetic heart. Instead, they investigated the role of the renin-angiotensin system (RAS) in mice with cardiac-specific overexpression of wild-type p90 ribosomal S6 kinase (WT-p90RSK-Tg). These mice also display increased PRECE levels as compared with nontransgenic littermate control mice (NLC). Recovery of cardiac function after ischemia/reperfusion in WT-p90RSK-Tg isolated hearts was significantly impaired. Both captopril and olmesartan improved cardiac function and reduced infarct size in WT-p90RSK-Tg mice, whereas these RAS blockers exerted no effect in NLC hearts.
Densitometric analysis revealed that angiotensinogen in WT-p90RSK-Tg (but not NLC) hearts decreased to undetectable levels within 10 minutes after the start of buffer perfusion. This corresponds with our earlier observation that angiotensinogen washout from buffer-perfused rat hearts occurs with a half-time of <3 minutes.3 A similarly rapid washout was observed for renin,3 and given the identical diffusion rates and receptor-binding kinetics of renin and prorenin,1 cardiac prorenin will likely disappear equally rapidly. Thus, after the 25-minute equilibration period applied by Itoh et al,2 it is unlikely that any (pro)renin or angiotensinogen remains in the isolated perfused heart. The authors claim that the more rapid angiotensinogen disappearance in the WT-p90RSK-Tg heart is suggestive of increased angiotensinogen–Ang I conversion. However, given the kinetics of the renin-angiotensinogen reaction (resulting in pmol/L angiotensin levels at μmol/L angiotensinogen concentrations), near-complete angiotensinogen–Ang I conversion in 10 minutes is very unlikely in our opinion.
To explain the beneficial effects of RAS blockers during ischemia/reperfusion in WT-p90RSK-Tg hearts that lack angiotensinogen (as opposed to the lack of effect of these drugs in NLC hearts, in which angiotensinogen washout occurred more slowly), the radical-scavenging properties of sulfhydryl-containing angiotensin-converting enzyme inhibitors (like captopril)4 and the antiarrhythmic (non–Ang II type 1 receptor-mediated) effects of Ang II type 1 receptor antagonists5 should be taken into consideration. Finally, direct angiotensinogen–Ang II conversion by PRECE, as suggested by the authors, seems unlikely, given the undetectable angiotensin levels in hearts of nephrectomized animals in vivo.1
The contribution of PRECE to prorenin-renin conversion in the diabetic heart should now be thoroughly investigated. The authors are to be complimented for providing a potential piece of the puzzle that links prorenin to tissue angiotensin generation.
Dr Danser is the recipient of a Novartis Aliskiren Grant and is a member of the Novartis Aliskiren Advisory Board. The other authors report no conflicts.
Danser AHJ, Deinum J. Renin, prorenin and the putative (pro)renin receptor. Hypertension. 2005: 46; 1069–1076.
Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, Abe J. Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium. Circulation. 2006; 113: 1787–1798.
de Lannoy LM, Danser AHJ, van Kats JP, Schoemaker RG, Saxena PR, Schalekamp MADH. Renin-angiotensin system components in the interstitial fluid of the isolated perfused rat heart: local production of angiotensin I. Hypertension. 1997; 29: 1240–1251.
Thomas GP, Ferrier GR, Howlett SE. Losartan exerts antiarrhythmic activity independent of angiotensin II receptor blockade in simulated ventricular ischemia and reperfusion. J Pharmacol Exp Ther. 1996; 278: 1090–1097.