Spontaneous Ischemic Events in the Brain and Heart Adapt the Hearts of Severely Atherosclerotic Mice to Ischemia

Abstract

Abstract-To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection. Key Words: ischemic preconditioning Ⅲ remote preconditioning Ⅲ atherosclerosis Ⅲ brain ischemia Ⅲ inducible nitric oxide synthase C ardiac adaptation to ischemia can be achieved experimentally by ischemic preconditioning, transient episodes of ischemia and reperfusion before sustained ischemia.

Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism

“…The concept of RPC extends memory from a temporal storage of information to a spatial storage of information because the recognition of ischemia and reperfusion in one tissue is transferred to a virginal tissue not subjected to such preceding episodes (17). Although circulating humoral factors and neuronal mechanisms are involved in the initiation and transfer of such information (3,6), our study shows that the information is memorized within the explanted heart independently of ongoing humoral and neuronal stimulation.…”

Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart

“…Only healthy mice without skin injuries and no neurological deficit were accepted for the study (Tokuno et al, 2002). WT and KO mice were heparinised and anesthetised with a mixture of fluanisonum, fentaylum and midazolam (2.5, 0.08 and 1.25 mg kg À1 , respectively, i.m.).…”

Remote preconditioning and delayed cardioprotection in skeletal muscle

“…These data agree with those previously observed in the explanted rat heart and suggest that opening mK ATP channels produces an energy-sparing effect during sustained ischemia in heart and skeletal muscle. These data also suggest that mK ATP channels are both a trigger and mediator of acute remote IPC in hindlimb skeletal muscle of rats and pigs.Despite a number of papers suggesting that remote IPC performed in different organs results in acute protection of distant organs against infarction, only two previous papers (19,20) suggested that remote IPC can result in delayed protection 24 -72 h later, similar to that of delayed IPC because of a local IPC stimulus. Wang et al (20) showed that intestinal preconditioning by ischemia resulted in a protective effect against myocardial infarction 24 h later and that this effect was…”

“…Despite a number of papers suggesting that remote IPC performed in different organs results in acute protection of distant organs against infarction, only two previous papers (19,20) suggested that remote IPC can result in delayed protection 24 -72 h later, similar to that of delayed IPC because of a local IPC stimulus. Wang et al (20) showed that intestinal preconditioning by ischemia resulted in a protective effect against myocardial infarction 24 h later and that this effect was mediated by inducible NO synthase (iNOS) based upon its blockade by two relatively selective iNOS inhibitors, aminoguanidine and S-methylthiourea.…”

“…Wang et al (20) showed that intestinal preconditioning by ischemia resulted in a protective effect against myocardial infarction 24 h later and that this effect was mediated by inducible NO synthase (iNOS) based upon its blockade by two relatively selective iNOS inhibitors, aminoguanidine and S-methylthiourea. More recently, Tokuno et al (19) showed that bilateral occlusion of the rat internal carotid arteries 24 h before studying their hearts in the Langedorff mode produced a reduction in infarct size and improved function, an effect also mediated by iNOS. Of course, this preconditioning protocol was not produced by brief occlusions of the carotid arteries, so these results are difficult to put in perspective with previous studies of remote IPC produced by brief periods of ischemia of a distant organ.…”