Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium.
BACKGROUND
Epidemiological data strongly indicate that diabetes increases the incidence of heart failure. Although the benefit of angiotensin-converting enzyme inhibitor (ACE-I) treatment during and after myocardial infarction has been found to be greater in diabetics than nondiabetics and activation of the renin-angiotensin system (RAS) has been implicated, the molecular basis of these actions remains unclear.


RESULTS
We generated transgenic mice with cardiac-specific overexpression of wild-type p90 ribosomal S6 kinase (WT-p90RSK-Tg) and a dominant-negative form of p90RSK (DN-p90RSK-Tg). Recovery of cardiac function after ischemia/reperfusion in WT-p90RSK-Tg isolated mouse hearts was significantly impaired. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry revealed specific induction of prorenin-converting enzyme (PRECE) in WT-p90RSK-Tg mice. mRNA induction of PRECE was confirmed with serial angiotensinogen protein reduction after perfusion in WT-p90RSK-Tg mice, suggesting an increase of angiotensinogen cleavage and subsequent RAS activation in WT-p90RSK-Tg mice. We investigated the role of the RAS in WT-p90RSK-Tg animals after ischemia/reperfusion with the use of an ACE-I (captopril) and an angiotensin II type 1 receptor blocker (olmesartan). We did not observe any effect of these inhibitors in non-Tg littermate controls, thus corroborating other reports in rodents. In contrast, both captopril and olmesartan significantly improved cardiac function and reduced infarct size in WT-p90RSK-Tg mice. At 8 months of age, WT-p90RSK-Tg mice developed cardiac dysfunction. p90RSK activity and PRECE mRNA were both increased by streptozotocin-induced hyperglycemia in non-Tg littermate controls, whereas DN-p90RSK-Tg animals exposed to streptozotocin did not have PRECE induction.


CONCLUSIONS
This study demonstrates the critical role of p90RSK in hyperglycemia-mediated myocardial PRECE induction, which may explain the augmentation of the RAS in diabetic hearts and provide an alternative therapeutic approach to treat diabetic cardiomyopathy.
Itoh
Seigo
S
Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA.
Ding
Bo
B
Shishido
Tetsuro
T
Lerner-Marmarosh
Nicole
N
Wang
Nadan
N
Maekawa
Naoya
N
Berk
Bradford C
BC
Takeishi
Yasuchika
Y
Yan
Chen
C
Blaxall
Burns C
BC
Abe
Jun-ichi
J
D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology; D009202:Cardiomyopathies / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D006439:Hemodynamics; D007610:Kallikreins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D017202:Myocardial Ischemia / Q000201:enzymology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology*; D012084:Renin-Angiotensin System / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
D038744:Ribosomal Protein S6 Kinases, 90-kDa; D007610:Kallikreins; C489124:Klk26 protein, mouse