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.
Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA.
Seigo
S
Itoh
Bo
B
Ding
Tetsuro
T
Shishido
Nicole
N
Lerner-Marmarosh
Nadan
N
Wang
Naoya
N
Maekawa
Bradford C
BC
Berk
Yasuchika
Y
Takeishi
Chen
C
Yan
Burns C
BC
Blaxall
Jun-ichi
J
Abe
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