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1.
Asanuma H Kitakaze M Funaya H Takashima S Minamino T Node K Sakata Y Asakura M Sanada S Shinozaki Y Mori H Kuzuya T Tada M Hori M 《Basic research in cardiology》2001,96(5):497-505
Objectives Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that nifedipine increases cardiac NO levels in the ischemic canine hearts, suggesting that nifedipine
may also have protective effects against ischemia and reperfusion injury, because the enhancement of NO production limits
infarct size. We tested whether nifedipine limits infarct size via NO-dependent mechanisms. Methods In open chest dogs, the left anterior descending coronary artery was perfused with blood through a bypass tube and occluded
for 90 min followed by 6 hours of reperfusion. Infarct size was assessed at 6 hours of reperfusion. Nifedipine of 3 or 6 μg/kg/min
was infused into the bypass tube between 10 min prior to the onset of ischemia and 60 min of reperfusion. Results Neither systemic blood pressure nor heart rate changed during infusion of nifedipine. Infarct size was reduced by the administration
of nifedipine (3 or 6 μg/kg/min) compared with the untreated condition (25.6 plusmn; 2.6 and 19.1 ± 3.5 vs. 43.4 ± 5.6 %,
respectively), which was completely blunted by L-NAME (45.0 ± 3.6 and 45.4 ± 4.2 vs. 47.9 ± 3.9 % in the nifedipine (3 or
6 μg/kg/min) with L-NAME groups vs. the L-NAME group). Myeloperoxidase activity of the myocardium increased after 6 hours
of reperfusion, which was attenuated by nifedipine. The limitation of infarct size and the attenuation in myeloperoxidase
activity were completely blunted by L-NAME. There were no significant differences in collateral blood flow at 45 min of ischemia
between each group. Conclusions We conclude that the Ca channel blocker, nifedipine, limits infarct size via NO-dependent mechanisms.
Received: 21 September 2000, Returned for 1. revision: 9 October 2000, 1. Revision received: 17 January 2001, Returned for
2. revision: 5 February 2001, 2. Revision received: 13 February 2001, Accepted: 14 February 2001 相似文献
2.
Ghaboura N Tamareille S Ducluzeau PH Grimaud L Loufrani L Croué A Tourmen Y Henrion D Furber A Prunier F 《Basic research in cardiology》2011,106(1):147-162
Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia–reperfusion (I/R) injury through
activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and
insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes
and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced
diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or
120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion.
In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated
and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3β. In hearts from STZ-induced
diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat
hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3β. In contrast, in hearts from HFD-induced
insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts,
respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3β. Administration of GSK-3β inhibitor SB216763 was cardioprotective
in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption
of upstream signaling of GSK-3β. In conclusion, direct inhibition of GSK-3β may provide an alternative strategy to protect
diabetic hearts against I/R injury. 相似文献
3.
Hirata A Minamino T Asanuma H Sanada S Fujita M Tsukamoto O Wakeno M Myoishi M Okada K Koyama H Komamura K Takashima S Shinozaki Y Mori H Tomoike H Hori M Kitakaze M 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2005,19(1):33-40
Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size (high dose (1,000 IU/kg): 7.7 ± 1.6%, low dose (100 IU/kg): 22.1 ± 2.4%, control: 40.0 ± 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion (high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction. 相似文献
4.
Wang Z Li M Wu WK Tan HM Geng DF 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2008,22(6):443-452
Background Ginsenoside Rb1, a major bioactive component of Panax ginseng, bears various beneficial effects on the cardiovascular system. This study investigated whether ginsenoside Rb1 preconditioning
has protective effects on myocardial ischemia–reperfusion injury and its potential mechanism.
Methods Rats subjected to 45 min of myocardial ischemia followed by 120 min of reperfusion were assigned to the following groups:
sham-operated, ischemia–reperfusion (I/R), ginsenoside Rb1+I/R, wortmannin(a specific PI3K inhibitor)+I/R, wortmannin drug
vehicle (dimethyl sulfoxide, DMSO), wortmannin+sham, ginsenoside Rb1+ wortmannin +I/R. Infarct size was assessed by triphenyltetrazolium
chloride staining. Plasma creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactate dehydrogenase (LDH), and troponin
T levels were also measured. Akt phosphorylation expression was assessed by immunoblotting.
Results Ginsenoside Rb1 preconditioning reduced infarct size compared with that in the I/R group: 30 ± 2.6% versus 51 ± 2.7% (p < 0.01). Ginsenoside Rb1 preconditioning also markedly reduced the plasma CK, CK-MB, LDH and troponin T levels in blood.
Akt phosphorylation expression increased after ginsenoside Rb1 preconditioning. These effects of ginsenoside Rb1 preconditoning
were significantly inhibited by wortmannin.
Conclusion This is the first study to demonstrate that ginsenoside Rb1 preconditioning has protective effects on myocardial ischemia
and reperfusion injury, partly by mediating the activation of the PI3K pathway and phosphorylation of Akt.
Project supported by the National Basic Research Program of China (a.k.a. 973 Program) (No.2005CB523305). 相似文献
5.
Because tyrosine kinase blockade prevents protection by ischemic preconditioning (PC) in several species, activation of
tyrosine kinase appears to be critical for cardioprotection. The tyrosine kinase's identity, however, is unknown. The present
study tested whether activation of a receptor tyrosine kinase, the insulin receptor, could mimic PC and if the mechanism of
protection was similar to that of PC. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion.
Infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Infarct size
in control hearts was 32.6 ± 2.3 %. A 5-min infusion of insulin (5 mU/ml) followed by a 10-min washout period prior to ischemia
significantly reduced infarction to 14.7 ± 2.1 % (P < 0.05). The tyrosine kinase inhibitor genistein (50 μM) given around the insulin infusion blocked protection (28.9 ± 2.8
%). However, when present during the onset of ischemia, genistein had no effect on protection triggered by insulin (14.0 ±
2.4 %; P < 0.05). Inhibition of either PKC by polymyxin B (50 μM) or KATP channels by 5-hydroxydecanoate (100 μM) also failed to prevent protection by insulin (17.5 ± 3.2 % and 17.6 ± 3.0 %, respectively).
However, the reduction in infarct size by insulin was significantly attenuated by wortmannin (100 nM), a selective inhibitor
of phosphatidylinositol 3-kinase (P13K, 28.3 ± 2.2 %). Insulin was still able to protect the heart when given only during
the reperfusion period (13.2 ± 3.4 %). PC reduced infarction to 12.8 ± 2.0 % (P < 0.05). In conclusion, activation of the insulin receptor reduces infarct size in the rabbit heart even when instituted
upon reperfusion. However, the mechanism of protection is quite different from that of PC and involves activation of P13K
but not PKC or KATP channels.
Received: 12 November 1998, Returned for revision: 25 November 1998, Revision received: 8 December 1998, Accepted: 10 December
1998 相似文献
6.
Sato T Tanno M Miki T Yano T Sato T Shimamoto K Miura T 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2010,24(5-6):401-408
Purpose
Erythropoietin (EPO) and its non-erythrogenic derivative, carbarmylated EPO (CEPO), have been reported to activate different receptors (homomeric EPO receptor vs. heteromeric receptor consisting of EPO receptor monomer and common β-subunit). The aim of this study was to examine differences between EPO and CEPO in efficacy of cardioprotection against infarction and in activation of pro-survival kinases.Methods
In isolated rat hearts, infarction was induced by global ischemia followed by reperfusion. Infarct size was determined 2 h after reperfusion, and ventricular tissues for immunoblotting were sampled at 5 min after reperfusion.Results
Pretreatment with EPO (10 units/ml) before ischemia reduced infarct size (% of risk area; %IS/AR) from 47.0?±?2.1% of the control after 20-min ischemia to 24.7?±?4.3% and from 62.0?±?3.0% after 25-min ischemia to 45.5?±?4.1%. Desialylated EPO (asialoEPO, 100 ng/ml) mimicked the protection by EPO. However, CEPO (100 ng/ml) failed to reduce infarct size after 20-min ischemia (%IS/AR?=?47.5?±?5.9%) and that after 25-min ischemia (%IS/AR?=?56.1?±?4.2%). The infarct size-limiting effect of CEPO was not shown either by increasing CEPO dose to 500 ng/ml or by shortening ischemia to 15 min. Both EPO and CEPO enhanced phosphorylation of cytosolic GSK-3β upon reperfusion. In contrast, phosphorylation of GSK-3β, Akt, and PKC-ε in mitochondria upon reperfusion was significantly enhanced by EPO but not by CEPO.Conclusion
EPO affords more potent protection against infarction than does CEPO by distinct activation of signaling leading to phosphorylation of pro-survival protein kinases in mitochondria upon reperfusion. 相似文献7.
Natriuretic peptides are regulatory autacoids in the mammalian myocardium whose functions, mediated via particulate guanylyl
cyclase/cGMP, may include cytoprotection against ischaemia-reperfusion injury. Previous work has identified that B-type natriuretic
peptide (BNP) limits infarct size when administered prior to and during coronary occlusion through a KATP channel-dependent mechanism. The present study examined the hypothesis that the protection afforded by BNP is mediated specifically
at reperfusion in a postconditioning-like manner. Langendorff-perfused rat hearts were subjected to 35 min coronary artery
occlusion and 120 min reperfusion, and infarct size was determined by tetrazolium staining. Postconditioning was effected
by applying six 10-second periods of global ischaemia at the onset of reperfusion.Treatment with either BNP 10 nM or the NO
donor S-nitroso-N-acetylpenicillamine (SNAP) 1–10 μM was commenced 5 min prior to reperfusion and continued until 10 min after
reperfusion. Control infarct size (% of ischaemic risk zone) was 40.8 ± 3.7%.BNP at reperfusion induced a significant limitation
of infarct size (BNP 22.9 ± 4.1% P<0.05 vs. control). Co-treatment at reperfusion with BNP and the KATP channel blockers 5-hydroxydecanote (5HD, 100 μM), glibenclamide (Glib; 10 μM) or HMR1098 (10 μM) abolished the infarct-limiting
effect of BNP (BNP + 5HD 41.0 ± 3.9%, BNP + Glib 39.8 ± 5.6%, BNP + HMR 1098 46.0 ± 7.1%,P < 0.05 vs. BNP). BNP given together
with L-NAME (100 μM) at reperfusion resulted in a marked loss of protection (BNP + L-NAME 53.1 ± 3.8% P < 0.001 vs. BNP).
In a second series of experiments, SNAP (1–10 μM) given at reperfusion was found not to be protective (SNAP 1 μM 30.2 ± 4.9%,
SNAP 2 μM 27.5 ± 9.5%, SNAP 5 μM 39.2 ± 5.7%, SNAP 10 μM 33.7 ± 6.4%, not significant vs. control). In a third series of experiments,
postconditioning significantly limited infarct size (14.9 ± 3.6 % vs. control 34.5 ± 4.9%, P < 0.01) and this effect of postconditioning
was abolished in the presence of isatin (100 μM), a non-specific blocker of particulate guanylyl cyclases (35.1 ± 6%, P <
0.05 vs. postconditioning). In conclusion, pharmacological activation of pGC by BNP can effectively induce protection against
reperfusion injury, by mechanisms involving KATP channel opening and endogenous NO synthase activation. Furthermore, endogenous activation of pGC could play a role in the
mechanism of postconditioning. 相似文献
8.
Tamareille S Mateus V Ghaboura N Jeanneteau J Croué A Henrion D Furber A Prunier F 《Basic research in cardiology》2011,106(6):1329-1339
Local ischemic postconditioning (IPost) and remote ischemic perconditioning (RIPer) are promising methods to decrease ischemia–reperfusion
(I/R) injury. We tested whether the use of the two procedures in combination led to an improvement in cardioprotection through
a higher activation of survival signaling pathways. Rats exposed to myocardial I/R were allocated to one of the following
four groups: Control, no intervention at myocardial reperfusion; IPost, three cycles of 10-s coronary artery occlusion followed
by 10-s reperfusion applied at the onset of myocardial reperfusion; RIPer, 10-min limb ischemia followed by 10-min reperfusion
initiated 20 min after coronary artery occlusion; IPost+RIPer, IPost and RIPer in combination. Infarct size was significantly
reduced in both IPost and RIPer (34.25 ± 3.36 and 24.69 ± 6.02%, respectively) groups compared to Control (54.93 ± 6.46%,
both p < 0.05). IPost+RIPer (infarct size = 18.04 ± 4.86%) was significantly more cardioprotective than IPost alone (p < 0.05). RISK pathway (Akt, ERK1/2, and GSK-3β) activation was enhanced in IPost, RIPer, and IPost+RIPer groups compared
to Control. IPost+RIPer did not enhance RISK pathway activation as compared to IPost alone, but instead increased phospho-STAT-3
levels, highlighting the crucial role of the SAFE pathway. In IPost+RIPer, a SAFE inhibitor (AG490) abolished cardioprotection
and blocked both Akt and GSK-3β phosphorylations, whereas RISK inhibitors (wortmannin or U0126) abolished cardioprotection
and blocked STAT-3 phosphorylation. In our experimental model, the combination of IPost and RIPer improved cardioprotection
through the recruitment of the SAFE pathway. Our findings also indicate that cross talk exists between the RISK and SAFE pathways. 相似文献
9.
Ruiz-Meana M Inserte J Fernandez-Sanz C Hernando V Miro-Casas E Barba I Garcia-Dorado D 《Basic research in cardiology》2011,106(6):1259-1268
Mitochondrial permeability transition (MPT) is critical in cardiomyocyte death during reperfusion but it is not the only mechanism
responsible for cell injury. The objectives of the study is to investigate the role of the duration of myocardial ischemia
on mitochondrial integrity and cardiomyocyte death. Mitochondrial membrane potential (ΔΨm, JC-1) and MPT (calcein) were studied
in cardiomyocytes from wild-type and cyclophilin D (CyD) KO mice refractory to MPT, submitted to simulated ischemia and 10 min
reperfusion. Reperfusion after 15 min simulated ischemia induced a rapid recovery of ΔΨm, extreme cell shortening (contracture)
and mitochondrial calcein release, and CyD ablation did not affect these changes or cell death. However, when reperfusion
was performed after 25 min simulated ischemia, CyD ablation improved ΔΨm recovery and reduced calcein release and cell death
(57.8 ± 4.9% vs. 77.3 ± 4.8%, P < 0.01). In a Langendorff system, CyD ablation increased infarct size after 30 min of ischemia (61.3 ± 6.4% vs. 45.3 ± 4.0%,
P = 0.02) but reduced it when ischemia was prolonged to 60 min (52.8 ± 8.1% vs. 87.6 ± 3.7%, P < 0.01). NMR spectroscopy in rat hearts showed a rapid recovery of phosphocreatine after 30 min ischemia followed by a marked
decay associated with contracture and LDH release, that were preventable with contractile blockade but not with cyclosporine
A. In contrast, after 50 min ischemia, phosphocreatine recovery was impaired even with contractile blockade (65.2 ± 4% at
2 min), and cyclosporine A reduced contracture, LDH release and infarct size (52.1 ± 4.2% vs. 82.8 ± 3.6%, P < 0.01). In conclusion, the duration of ischemia critically determines the importance of MPT on reperfusion injury. Mechanisms
other than MPT may play an important role in cell death after less severe ischemia. 相似文献
10.
Takahama H Minamino T Hirata A Ogai A Asanuma H Fujita M Wakeno M Tsukamoto O Okada K Komamura K Takashima S Shinozaki Y Mori H Mochizuki N Kitakaze M 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2006,20(3):159-165
Purpose Recent studies suggest that G-CSF prevents cardiac remodeling following myocardial infarction (MI) likely through regeneration
of the myocardium and coronary vessels. However, it remains unclear whether G-CSF administered at the onset of reperfusion
prevents ischemia/reperfusion injury in the acute phase. We investigated acute effects of G-CSF on myocardial infarct size
and the incidence of lethal arrhythmia and evaluated the involvement of the phosphatidylinositol-3 kinase (PI3K) in the in vivo canine models.
Methods In open-chest dogs, left anterior descending coronary artery (LAD) was occluded for 90 minutes followed by 6 hours of reperfusion.
We intravenously administered G-CSF (0.33 μ/kg/min) for 30 minutes from the onset of reperfusion. Wortmannin, a PI3K inhibitor,
was selectively administered into the LAD after the onset of reperfusion.
Results G-CSF significantly (p<0.05) reduced myocardial infarct size (38.7±4.3% to 15.7±5.3%) and the incidence of ventricular fibrillation during reperfusion
periods (50% to 0%) compared with the control. G-CSF enhanced Akt phospholylation in ischemic canine myocardium. Wortmannin
blunted both the infarct size-limiting and anti-arrhythmic effects of G-CSF. G-CSF did not change myeloperoxidase activity,
a marker of neutrophil accumulation, in the infarcted myocardium.
Conclusion An intravenous administration of G-CSF at the onset of reperfusion attenuates ischemia/reperfusion injury through PI3K/Akt
pathway in the in vivo model. G-CSF administration can be a promising candidate for the adjunctive therapy for patients with acute myocardial infarction.
Takahama and Hirata contributed equally to this work. 相似文献
11.
Aitchison KA Baxter GF Awan MM Smith RM Yellon DM Opie LH 《Basic research in cardiology》2000,95(1):1-10
δ-Opioid receptors are known to participate in the protection found following ischemic preconditioning (IPC), but the role
of κ-receptors in IPC is currently controversial. Langendorff-perfused rat hearts received 35 min regional ischemia and 2
h reperfusion. PC (2 cycles 5 min global ischemia) substantially reduced infarct size. Pharmacological PC with the δ-agonist
DADLE (10 nmol/L) had similar protective effects. However, higher dose DADLE (1 μmol/L) had a less beneficial effect, and
in conjunction with the δ-antagonist naltrindole unexpectedly increased infarct size (61.5 ± 2.0%, p < 0.05 v 45.9 ± 2.3%
in controls) sugggesting a non-δ effect. The universal κ-opioid agonist bremazocine (30 nmol/L) increased infarct size (61.3
± 1.6%, p < 0.05 v controls), an effect abrogated by the selective κ1-antagonist nor-binaltorphimine (BNI).
Since opiates are known to have anti-adrenergic effects, which hypothetically may help to mediate IPC, cyclic AMP levels were
measured in DADLE and in bremazocine-treated hearts. Decreased levels of cyclic AMP at the start of the regional ischemic
period were found in low dose DADLE hearts (0.485 ± 0/020, n = 8, vs controls, 0.654 ± 0.025 nmol/g wet weight, p < 0.001),
but not in high dose DADLE nor in bremazocine treated hearts.
Thus, in the isolated rat heart κ1-opioid receptor activation exacerbates infarct size through an as yet unknown mechanism, suggesting that there could be an
“anti-preconditioned state”. In contrast, δ-activity mediates protection which may be associated with a reduction of tissue
cyclic AMP levels.
Received: 16 November 1999, Accepted: 7 December 1999 相似文献
12.
Long-term inhibition of myocardial
infarction by postconditioning
during reperfusion 总被引:7,自引:0,他引:7
Mykytenko J Kerendi F Reeves JG Kin H Zatta AJ Jiang R Guyton RA Vinten-Johansen J Zhao ZQ 《Basic research in cardiology》2007,102(1):90-100
Cardioprotection with postconditioning has been well demonstrated
after a short period of reperfusion. This study tested the hypothesis
that postconditioning reduces infarct size, vascular dysfunction, and neutrophil
accumulation after a long-term reperfusion. Canines undergoing 60
min left anterior descending artery (LAD) occlusion were divided into two
control groups of either 3 h or 24 h of full reperfusion and two postconditioning
groups with three 30 s cycles of reperfusion and re-occlusion applied
at the onset of either 3 h or 24 h of reperfusion. Size of the area at risk (AAR)
and collateral blood flow during ischemia were similar among groups. In
controls, infarct size as percentage of the AAR (30 ± 3 vs. 39 ± 2* %) by TTC
staining, superoxide anion generation from the post-ischemic coronary arteries
by lucigenin-enhanced chemiluminescence [(89 ± 5 vs. 236 ± 27* relative
light units (RLU/mg)], and neutrophil (PMN) accumulation by immunohistochemical
staining in the AAR (52 ± 11 vs. 84 ± 14* cells/mm2
myocardium) significantly increased between 3 and 24 h of reperfusion.
Postconditioning reduced infarct size (15 ± 4† and 27 ± 3.6† %), superoxide
anion generation (24 ± 4† and 43 ± 11† RLU/mg), and PMN accumulation
(19 ± 6† and 45 ± 8† cells/mm2 myocardium) in the 3 and 24 h reperfusion
groups relative to time-matched controls. These data suggest that myocardial
injury increases with duration of reperfusion; reduction in infarct size
and attenuation in inflammatory responses with postconditioning persist after
a prolonged reperfusion. * p < 0.05 24 vs. 3 h control; † p < 0.05 postconditioning
vs. time-matched control. 相似文献
13.
Lim SY Davidson SM Mocanu MM Yellon DM Smith CC 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2007,21(6):467-469
Background Necrostatin (Nec-1) protects against ischemia–reperfusion (IR) injury in both brain and heart. We have previously reported
in this journal that necrostatin can delay opening of the mitochondrial permeability transition pore (MPTP) in isolated cardiomyocytes.
Aim The aim of the present study was to investigate in more detail the role played by the MPTP in necrostatin-mediated cardioprotection
employing mice lacking a key component of the MPTP, namely cyclophilin-D.
Method Anaesthetized wild type (WT) and cyclophilin-D knockout (Cyp-D−/−) mice underwent an open-chest procedure involving 30 min
of myocardial ischemia and 2 h of reperfusion, with subsequent infarct size assessed by triphenyltetrazolium staining. Nec-1,
given at reperfusion, significantly limited infarct size in WT mice (17.7 ± 3% vs. 54.3 ± 3%, P < 0.05) but not in Cyp-D−/− mice (28.3 ± 7% vs. 30.8 ± 6%, P > 0.05).
Conclusion The data obtained in Cyp-D−/− mice provide further evidence that Nec-1 protects against myocardial IR injury by modulating
MPTP opening at reperfusion. 相似文献
14.
Garcia S Henry TD Wang YL Chavez IJ Pedersen WR Lesser JR Shroff GR Moore L Traverse JH 《Journal of cardiovascular translational research》2011,4(1):92-98
Reperfusion injury may offset the optimal salvage of myocardium achieved during primary coronary angioplasty. Thus, coronary
reperfusion must be combined with cardioprotective adjunctive therapies in order to optimize myocardial salvage and minimize
infarct size. Forty-three patients with their first ST-elevation myocardial infarction were randomized to myocardial postconditioning
or standard of care at the time of primary coronary angioplasty. Postconditioning was performed immediately upon crossing
the lesion with the guide wire and consisted of four cycles of 30 s occlusion followed by 30 s of reperfusion. End-points
included infarct size, myocardial perfusion grade (MPG), left-ventricular ejection fraction (LVEF), and long-term clinical
events (death and heart failure). Despite similar ischemic times (≅4.5 h) (p = 0.9) a reduction in infarct size was observed among patients treated with the postconditioning protocol. Peak creatine
phosphokinase (CPK), as well as its myocardial band (MB) fraction, was significantly lower in the postconditioning group when
compared with the control group (CPK—control, 2,444 ± 1,928 IU/L vs. PC, 2,182 ± 1,717 IU/L; CPK-MB—control, 242 ± 40 IU/L
vs. PC, 195 ± 33 IU/L; p = 0.64 and p < 0.01, respectively). EF in the postconditioning group was improved when compared with the control group (control, 43% ± 15
vs. PC, 52% ± 9; p = 0.05). After a mean follow-up of 3.4 years, a 6-point absolute difference in LVEF was still evident in the postconditioning
group (p = 0.18). MPG was better among patients treated with the postconditioning protocol compared with control (2.5 ± 0.5 vs. 2.1 ± 0.6;
p = 0.02). Due to the small sample size no significant differences in clinical events were detected (p value for death = 0.9; p value for heart failure = 0.2). A simple postconditioning protocol applied at the onset of mechanical reperfusion, resulted
in reduction of infarct size, better epicardial and myocardial flow, and improvement in left ventricular function. The beneficial
effects of postconditioning on cardiac function persist beyond 3 years. 相似文献
15.
Antje Hönisch Norman Theuring Bernd Ebner Claudia Wagner Ruth H. Strasser Christof Weinbrenner 《Basic research in cardiology》2010,105(2):155-167
Reperfusion injury is strongly involved in the loss of functional heart tissue in patients after acute myocardial infarction.
Various signal transduction pathways to reduce infarct size during reperfusion have been characterized. However, so far in
the clinical setting no standard therapies are applied due to the lack of suitable drugs. Levosimendan, a calcium sensitizer,
has been shown to improve survival in cardiogenic shock after infarction. Focus of the present study was to address the question,
whether a bolus application of levosimendan prior to reperfusion is able to reduce the infarct size. A well-characterized
model, the in vivo rat model, was used and levosimendan applied 5 min prior to reperfusion after 30-min occlusion of the left
coronary artery followed by a 30-min reperfusion period. This pharmacological postconditioning was compared to the ischemic
postconditioning with three times occlusion/reperfusion periods of 30 s each. To further address the question if in this in
vivo model the phosphatidylinositol 3-kinase (PI3K) pathway may be involved, the PDE-III inhibiting property of levosimendan
was compared to the PDE-III inhibitor enoximone. Ischemic postconditioning significantly reduced the infarct size from 48 ± 2
to 32 ± 1% of the area at risk (P < 0.05). Similarly, levosimendan decreased infarct size down to 29 ± 3%. The combination of ischemic postconditioning and
pharmacological postconditioning using levosimendan did not result in a further reduction of the infarct size. Both, the mitochondrial
KATP-channel blocker 5-hydroxydecanoate (5-HD) and the PI3K inhibitor wortmannin abolished the protection afforded by levosimendan
completely, while the inhibitors alone did not influence the infarct size in control hearts. Pharmacological postconditioning
with enoximone did not result in any infarct size reduction. Postconditioning with levosimendan significantly increased the
phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β) at 5 min of reperfusion, an effect which
could be blocked completely by the additional administration of wortmannin. In conclusion, levosimendan applied prior to reperfusion
in acute myocardial infarction significantly reduces the infarct size in an in vivo rat model. This protection involves the
PI3K pathway and the activation of mitochondrial KATP-channels, but is independent of PDE-III inhibition. This finding may
open new possibilities for the treatment of patients with acute myocardial infarction using levosimendan, which is an already
established therapy in cardiogenic shock. Whether the reduction of mortality in cardiogenic shock by levosimendan may in part
be based on this postconditoning effect remains to be elucidated in clinical setting. 相似文献
16.
Protection from postconditioning depends on the number of short ischemic insults in anesthetized pigs 总被引:3,自引:0,他引:3
Iliodromitis EK Georgiadis M Cohen MV Downey JM Bofilis E Kremastinos DT 《Basic research in cardiology》2006,101(6):502-507
Abstract
Postconditioning in the early reperfusion period confers protection to the heart after a potentially lethal episode of prolonged
ischemia. Protection from this novel intervention has been documented in rat, rabbit and canine hearts, but one group has
reported that it is ineffective in pigs, a large-animal species that should be most relevant to humans. We hypothesized that
this negative result was related to an inappropriate postconditioning protocol rather than the species. The present study,
therefore, tested whether an effective postconditioning protocol could be identified that limits infarct size in anesthetized
pigs. Domestic Landrace pigs weighing 25–29 kg were anesthetized, and after a mid-sternal thoracotomy and pericardiotomy the
left anterior descending coronary artery was ligated for 60 min followed by 3 h of reperfusion. Three groups were studied:
control group (n = 5) with no other intervention, 4–30 PostC group (n = 5) with 4 cycles of 30-s reperfusion/30-s ischemia, and 8–30 PostC group (n = 6) with 8 cycles of 30-s reperfusion/30-s ischemia. The two postconditioning protocols started immediately after termination
of the 60-min coronary occlusion. Region at risk and infarct size were delineated with the aid of pre-mortem monastral blue
injection and postmortem staining with triphenyltetrazolium chloride, respectively. In control hearts 33.5 ± 7.6% of the risk
zone infarcted and 36.7 ± 3.7% in the 4–30 PostC group (P = NS). But there was only 10.5 ± 0.5% infarction in the 8–30 PostC group (P < 0.01 vs. the other two groups). Postconditioning confers protection in pigs but requires more than 4 ischemia/reperfusion
cycles. Postconditioning may protect by inhibiting mitochondrial permeability transition pore formation by keeping the heart
acidotic as it is reoxygenated. If true, then it would be difficult to employ too many occlusion cycles. 相似文献
17.
SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts 总被引:5,自引:0,他引:5
There is debate concerning the involvement of p38 mitogen-activated protein kinase (MAPK) in ischemic preconditioning (PC).
At the center of the controversy are data obtained after administration of SB 203580, a specific inhibitor of p38 MAPK. Whereas
several studies have reported that SB 203580 abolishes the cardioprotective effect of PC, others claim that this compound
is actually cardioprotective against ischemia. Many of these latter observations have been made in isolated myocardial cells.
Accordingly the present study was designed to test the effect of SB 203580 in a model of preconditioning in intact rabbit
hearts in which infarct size was the end-point. Isolated hearts experienced 30 min of regional ischemia followed by 120 min
of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.2 ± 3.3%
of the risk zone. PC with 5 min of global ischemia and 10 min of reperfusion before the 30-min period of ischemia significantly
reduced infarct size to 10.2 ± 2.4% (P < 0.05 vs. control). SB 203580 (2 μ M) added to the perfusate for 20 min starting 5
min before the index ischemia totally blocked the protection from PC (27.4 ± 3.3% infarction). SB 203580 alone had no effect
on infarct size (28.6 ± 4.6% infarction). These results reveal that SB 203580 does not affect infarct size on its own, but
selectively blocks preconditioning's anti-infarct effect in the intact rabbit heart.
Received: 21 August 2000, Returned for revision: 30 August 2000, Revision received: 2000, Accepted: 6 September 2000 相似文献
18.
Huan-Xin Zhao Xiao-Liang Wang Ye-Hong Wang Ye Wu Xiao-Yu Li Xiao-Ping Lv Zhi-Qing Zhao Rong-Rui Zhao Hui-Rong Liu 《Basic research in cardiology》2010,105(1):109-118
Postconditioning (PostC) has regenerated interest as a mechanical intervention against myocardial ischemia/reperfusion injury,
but its molecular mechanisms remain elusive. This study tested the hypothesis that hypoxia inducible factor-1α (HIF-1α) plays
a role in PostC-induced cardioprotection. Male Wistar rats were subjected to 30 min ischemia followed by 3 h of reperfusion
(Control). PostC with 3 cycles of 10 s reperfusion and 10 s re-occlusion was applied at the onset of reperfusion. Relative
to the Sham group, HIF-1α protein level was increased by 2.9-fold in the Control group, but its level was enhanced by 5.8-fold
with PostC (P < 0.01 vs. Control). However, HIF-1α protein level was further augmented by 2.0-fold and 3.3-fold, respectively, when the
prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG, 40 mg/kg, i.p.) was given at 24 h before ischemia in both Control
and PostC groups. PostC reduced infarct size by 24% compared with the Control (27 ± 4.2% vs. 36 ± 5.2%, P < 0.01), consistent with significant lower levels of plasma creatine kinase activity, index of cardiomyocyte apoptosis and
caspase-3 activity. Although pretreatment with DMOG significantly reduced infarct size relative to the Control, the infarct-sparing
effect of PostC was remarkably enhanced when DMOG was given before PostC (18 ± 2.0% vs. 27 ± 4.2% in PostC alone, P < 0.05). There was a significant linear inverse relationship between HIF-1α protein level and infarct size (r = −0.799, P < 0.01) among all groups. Furthermore, along with up-regulated HIF-1α expression, the levels of iNOS mRNA and protein were
significantly increased in the PostC alone and DMOG plus PostC groups. In conclusion, these data suggest that HIF-1α is involved
in cardioprotection by PostC and pharmacological augmentation of HIF-1α expression that enhances the infarct-sparing effect
of PostC; iNOS, the downstream gene of HIF-1α, may participate in signaling pathways in mediating PostC’s protection. 相似文献
19.
Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo 总被引:13,自引:0,他引:13
Objective
Erythropoietin (EPO) is a hormone that is currently
used to treat patients with renal failure and anaemia. However, it has also
been shown to protect against ischaemia/reperfusion injury; this protection
occurring via activation of the ERK 1/2 and PI3K pathways. Since we have previously
shown activation of ERK 1/2 and PI3K to be important for protection
against reperfusion–induced injury in the myocardium, this study was
designed to investigate its effect in the myocardium using both an isolated
perfused rat heart and an in vivo rat recovery model of ischaemia–reperfusion.
Methods
Using an in vitro isolated rat heart model of 35 minutes
ischaemia and 2 hours reperfusion, EPO (50 ng/ml) was administered to the
rat myocardium 5 minutes prior to reperfusion for 20 minutes. The in vivo
open–chest rat model consisted of 40 minutes ischaemia followed by 24 hours
reperfusion with EPO (5000 U/kg) being administered at the point of reperfusion.
Results
In the isolated perfused heart studies 50 ng/ml EPO was found
to provide protection with a % I/R of 22.9% ± 6.4 vs 54.5% ± 7.4 for the
ischaemic control group. To examine the mechanistic pathways involved in
EPO–mediated protection, we co–administered the ERK 1/2 inhibitor, U0126
(10 uM) or the PI3K inhibitors, wortmannin, (100 nM) and LY294002 (15 µM)
at reperfusion. U0126, wortmannin and LY294002 all abrogated EPO–mediated
protection (% I/R 49.2% ± 5.6, 46.1% ± 5.5 and 49.9% ± 6.1 respectively,
p < 0.05). In the in vivo open–chest rat model, the % I/R was significantly
attenuated in EPO–treated animals from 53.6 % ± 3.7 in the control to 32.5%
+/– 2.9 (p < 0.05). Likewise, wortmannin abrogated EPO–mediated protection
(% I/R 50.7 ± 2.3 v EPO 32.5% ± 2.9, p < 0.05).
Conclusion
We demonstrate
that EPO, administered at the point of reperfusion, reduced infarct size in an
isolated perfused rat heart, in an ERK and PI3K dependent manner; in addition
the mechanism was also confirmed in a whole animal model of
ischaemia–reperfusion. These results suggest that EPO may be able to directly
protect the myocardium against lethal reperfusion–induced injury and so
offer the myocardium an additional clinical advantage over and above its
ability to improve the oxygen carrying capacity of the blood. 相似文献
20.
Wangde Dai Sharon L. Hale Gregory L. Kay Aarne J. Jyrala Robert A. Kloner 《Cardiovascular therapeutics》2010,28(1):30-37
We determined the effects of olmesartan on infarct size and cardiac function in a rat ischemia/reperfusion model. Rats underwent 30 min of left coronary artery (CA) occlusion followed by 2 h of reperfusion. In protocol 1, the rats received (by i.v.) 1 mL of vehicle at 10 min after CA occlusion (Group 1, n = 15); olmesartan (0.3 mg/kg) at 10 min after CA occlusion (Group 2, n = 15); 1 mL of vehicle at 5 min before CA reperfusion (Group 3, n = 15); or olmesartan (0.3 mg/kg) 5 min before CA reperfusion (Group 4, n = 15). In protocol 2, the rats received (by i.v.) 1 mL of vehicle at 5 min before CA reperfusion (Group 5, n = 21); or olmesartan (3 mg/kg) at 5 min before CA reperfusion (Group 6, n = 21). Systemic hemodynamics, left ventricular (LV) function, LV ischemic risk zone, no‐reflow zone, and infarct size were determined. In protocol 1, olmesartan (0.3 mg/kg) did not affect blood pressure (BP), heart rate, LV ± dp/dt or LV fractional shortening during the experimental procedure, and did not alter no‐reflow or infarct size. In protocol 2, olmesartan (3 mg/kg) significantly reduced infarct size to 21.7 ± 4.1% from 34.3 ± 4.1% of risk zone in the vehicle group (P= 0.035), but did not alter the no‐reflow size. Prior to CA reperfusion, olmesartan (3 mg/kg) significantly reduced mean BP by 22% and LV ±dp/dt, but did not affect heart rate. At 2 h after reperfusion, olmesartan significantly decreased heart rate by 21%, mean BP by 14%, and significantly increased LV fractional shortening from 54.1 ± 1.4% to 61.3 ± 1.6% (P= 0.0018). Olmesartan significantly reduced myocardial infarct size and improved LV contractility at a dose (3 mg/kg) with systemic vasodilating effects but not at a lower dose (0.3 mg/kg) without hemodynamic effects. 相似文献