BACKGROUND: The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning. METHODS AND RESULTS: To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6+/-3% after RCS and 16+/-3% after SWIPC (both groups P<0.05, less than shams 42+/-4%). Two molecular signatures of SWIPC, the increased expression of the inducible isoform of nitric oxide synthase and the translocation of protein kinase Cepsilon to the plasma membrane, were observed with SWIPC but not with RCS. Confirming this, pretreatment with a nitric oxide synthase inhibitor prevented the protection conferred by SWIPC but not by RCS. Microarray analysis revealed a qualitatively different genomic profile of cardioprotection between ischemic preconditioning induced by RCS and that induced by SWIPC. The number of genes significantly regulated was greater in RCS (5739) than in SWIPC (2394) animals. Of the 5739 genes regulated in RCS, only 31% were also regulated in SWIPC. Broad categories of genes induced by RCS but not SWIPC included those involved in autophagy, endoplasmic reticulum stress, and mitochondrial oxidative metabolism. The upregulation of these pathways was confirmed by Western blotting. CONCLUSIONS: RCS induces cardioprotection against lethal myocardial ischemia that is at least as powerful as traditional ischemic preconditioning but is mediated through radically different mechanisms.
BACKGROUND: The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning. METHODS AND RESULTS: To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6+/-3% after RCS and 16+/-3% after SWIPC (both groups P<0.05, less than shams 42+/-4%). Two molecular signatures of SWIPC, the increased expression of the inducible isoform of nitric oxide synthase and the translocation of protein kinase Cepsilon to the plasma membrane, were observed with SWIPC but not with RCS. Confirming this, pretreatment with a nitric oxide synthase inhibitor prevented the protection conferred by SWIPC but not by RCS. Microarray analysis revealed a qualitatively different genomic profile of cardioprotection between ischemic preconditioning induced by RCS and that induced by SWIPC. The number of genes significantly regulated was greater in RCS (5739) than in SWIPC (2394) animals. Of the 5739 genes regulated in RCS, only 31% were also regulated in SWIPC. Broad categories of genes induced by RCS but not SWIPC included those involved in autophagy, endoplasmic reticulum stress, and mitochondrial oxidative metabolism. The upregulation of these pathways was confirmed by Western blotting. CONCLUSIONS: RCS induces cardioprotection against lethal myocardial ischemia that is at least as powerful as traditional ischemic preconditioning but is mediated through radically different mechanisms.
Authors: M Ashburner; C A Ball; J A Blake; D Botstein; H Butler; J M Cherry; A P Davis; K Dolinski; S S Dwight; J T Eppig; M A Harris; D P Hill; L Issel-Tarver; A Kasarskis; S Lewis; J C Matese; J E Richardson; M Ringwald; G M Rubin; G Sherlock Journal: Nat Genet Date: 2000-05 Impact factor: 38.330
Authors: Y Qiu; P Ping; X L Tang; S Manchikalapudi; A Rizvi; J Zhang; H Takano; W J Wu; S Teschner; R Bolli Journal: J Clin Invest Date: 1998-05-15 Impact factor: 14.808
Authors: Y Guo; W K Jones; Y T Xuan; X L Tang; W Bao; W J Wu; H Han; V E Laubach; P Ping; Z Yang; Y Qiu; R Bolli Journal: Proc Natl Acad Sci U S A Date: 1999-09-28 Impact factor: 11.205
Authors: Sebastian Wolfrum; Kathrin Schneider; Marc Heidbreder; Julie Nienstedt; Peter Dominiak; Andreas Dendorfer Journal: Cardiovasc Res Date: 2002-08-15 Impact factor: 10.787
Authors: H Takano; S Manchikalapudi; X L Tang; Y Qiu; A Rizvi; A K Jadoon; Q Zhang; R Bolli Journal: Circulation Date: 1998-08-04 Impact factor: 29.690
Authors: Monica Lisi; Matthias Oelze; Saverio Dragoni; Andrew Liuni; Sebastian Steven; Mary-Clare Luca; Dirk Stalleicken; Thomas Münzel; Franco Laghi-Pasini; Andreas Daiber; John D Parker; Tommaso Gori Journal: Clin Res Cardiol Date: 2012-06 Impact factor: 5.460
Authors: Christophe Depre; Ji Yeon Park; You-Tang Shen; Xin Zhao; Hongyu Qiu; Lin Yan; Bin Tian; Stephen F Vatner; Dorothy E Vatner Journal: Am J Physiol Heart Circ Physiol Date: 2010-06-25 Impact factor: 4.733
Authors: Li Chen; Paulo Lizano; Xin Zhao; Xiangzhen Sui; Sunil K Dhar; You-Tang Shen; Dorothy E Vatner; Stephen F Vatner; Christophe Depre Journal: Am J Physiol Heart Circ Physiol Date: 2011-02-11 Impact factor: 4.733
Authors: Claudio A Bravo; Dorothy E Vatner; Ronald Pachon; Jie Zhang; Stephen F Vatner Journal: J Pharmacol Exp Ther Date: 2016-03-03 Impact factor: 4.030
Authors: Claudio Bravo; Raymond K Kudej; Chujun Yuan; Seonghun Yoon; Hui Ge; Ji Yeon Park; Bin Tian; William C Stanley; Stephen F Vatner; Dorothy E Vatner; Lin Yan Journal: J Mol Cell Cardiol Date: 2012-11-02 Impact factor: 5.000
Authors: Dorothy E Vatner; Jie Zhang; Xin Zhao; Lin Yan; Raymond Kudej; Stephen F Vatner Journal: Am J Physiol Heart Circ Physiol Date: 2020-12-18 Impact factor: 4.733