Chronic angiotensin II receptor blockade induces cardioprotection during ischemia by increased PKC-epsilon expression in the mouse heart.
BACKGROUND
This study was performed to investigate the role of chronic pretreatment with angiotensin II type 1 receptor antagonists (ARB) and angiotensin converting enzyme inhibitors (ACE-I) in myocardial infarction (MI) and ischemic preconditioning (iPC). Little is known about molecular mechanisms of MI and iPC, especially about protein kinase C (PKC) isozyme levels induced by chronic pharmacologic pretreatment with ARB and ACE-I. To address one of the most important signal molecules in iPC, the PKC system was investigated in an ischemia/reperfusion model using isolated mouse hearts.


METHODS
C57/BL6 mice were treated orally with candesartan cilexetil or ramipril for 2 weeks. Isolated perfused hearts were subjected to 60 minutes of left anterior descending occlusion and 30 minutes of reperfusion. IPC was performed by 3 cycles of 5 minutes of ischemia prior to the infarct ischemia. Infarct size was measured using the propidium iodide method, and PKC isoenzymes were detected by immunoblotting in the membrane and cytosolic fraction.


RESULTS
In the control group, iPC reduced infarct size from 59.8 +/- 4.2% to 24.5 +/- 1.7%. ARB pretreatment itself reduced the infarct size significantly (38.1 +/- 3.0%) in hearts without iPC. This protection could neither be enhanced by additional iPC (40.3 +/- 3.4%) nor blocked by the AT2-receptor antagonist PD123.319 (40.7 +/- 3.7%). The ARB-induced cardio protection, however, was abolished by chelerythrine (5 micromol/L) (71.7 +/- 6.6%, n = 11, P < 0.001). Furthermore, PKC-epsilon (PKC-epsilon) was significantly increased in the particulate fraction of ARB-pretreated mice. On the contrary, chronic treatment with ACE-I completely blocked iPC (57.7 +/- 3.9%, n = 12, P < 0.001) without any effect on infarct size itself (51.5 +/- 3.0%, n = 12). PKC-epsilon expression was significantly reduced.


CONCLUSIONS
Chronic AT1-receptor antagonism is capable of protecting the heart against myocardial infarction in a PKC-epsilon-dependent way. Furthermore, chronic treatment with ACE-I is suggested to have suppressing effects on iPC, possibly caused by reduced PKC-epsilon expression.
Lange
Stefan A
SA
Department of Internal Medicine and Cardiology, Dresden University of Technology, Dresden, Germany. StefanALange@t-online.de
Wolf
Benita
B
Schober
Kristin
K
Wunderlich
Carsten
C
Marquetant
Rainer
R
Weinbrenner
Christof
C
Strasser
Ruth H
RH
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000188:drug therapy*; D009206:Myocardium / Q000201:enzymology*; D051744:Protein Kinase C-epsilon / Q000096:biosynthesis* / Q000235:genetics; D017257:Ramipril / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D051744:Protein Kinase C-epsilon; D017257:Ramipril; C077793:candesartan cilexetil