Cardiac contractile injury after intestinal ischemia-reperfusion

1991 ◽  
Vol 261 (4) ◽  
pp. H1164-H1170 ◽  
Author(s):  
J. W. Horton ◽  
D. J. White
Keyword(s):  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Multiorgan Failure ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
In Vivo Studies ◽  
Lv Function ◽  
Acid Base Balance ◽  
Cardiac Contractile ◽  
Sequence Of Events

Experimental and clinical data suggest that even a brief period of intestinal ischemia followed by reperfusion initiates a sequence of events that include release of inflammatory mediators and multiorgan failure. In this study, 41 rats were subjected to occlusion of the superior mesenteric artery (SMA) for 20 min and collateral arcade ligation. Twelve rats were sham operated and served as controls (group 1). Groups of rats with SMA occlusion were killed at several time intervals after reperfusion (group 2, 2-3 h; group 3, 4-5 h; group 4, 12-16 h). In group 5, rats were pretreated with enterally administered allopurinol (10 mg.kg-1.day-1) for 4 days before the intestinal ischemia episode and were studied 2-3 h after reperfusion. In vivo studies confirmed that 20 min of intestinal ischemia produced a transient bradycardia (P less than 0.05) and no change in systemic blood pressure, acid-base balance, or hematocrit. In vitro studies showed marked cardiac contractile depression as early as 2 h after ischemia-reperfusion as indicated by a fall in left ventricular pressure (LVP; from 77 +/- 3 to 63 +/- 4 mmHg, P = 0.01) and +dP/dtmax (from 1,827 +/- 59 to 1,557 +/- 99 mmHg/s, P less than 0.02) and -dP/dtmax (from 1,267 +/- 57 to 953 +/- 67 mmHg/s, P = 0.02), a rightward shift in LV function curves, and a decreased responsiveness to perfusate Ca2+. Allopurinol pretreatment prevented ischemia-reperfusion-mediated deficits in cardiac contraction and relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 405: Inhibition of Class I Histone Deacetylases at Reperfusion Attenuates Ischemia-reperfusion Injury and Modifies Mitochondrial Acetylation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Donald R Menick
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Mitochondrial Enzymes ◽  
Reperfusion Phase

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, much of the resultant damage occurs as a consequence of reperfusion itself. Previously, we have shown that pretreatment with MS-275, a selective class I histone deacetylase (HDAC) inhibitor, preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Here, we tested the hypothesis that MS-275 treatment at reperfusion reduces LV tissue damage and improves post-ischemic LV contractile function. To do this, hearts from male Sprague-Dawley rats were isolated and perfused ex vivo on a Langendorff perfusion apparatus. A saline-filled balloon was inserted into the left ventricle of the heart to monitor ventricular pressure development throughout the experiment. Hearts were subjected to 30 minutes of ischemia, followed by 60 minutes of reperfusion. MS-275 was administered during the entire reperfusion phase, and resultant functional data were compared to untreated hearts. There was no difference in any metric of pre-ischemic contractile function between groups. 10nM MS-275 administered at reperfusion significantly improved multiple measures of LV function, including dP/dtmax, -dP/dtmax, developed pressure and rate pressure product. We also observed a significant reduction in infarct area of treated hearts compared to control, as measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Unexpectedly, mass spectrometry analysis revealed significant changes in acetylation state of multiple mitochondrial enzymes. Administration of MS-275 during the reperfusion phase of IR is sufficient to partially rescue LV function from reperfusion-induced damage. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion.

Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2018 ◽  
Vol 132 (15) ◽  
pp. 1669-1683 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Lv Function ◽  
Male Wistar Rats ◽  
Group A

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion

2000 ◽  
Vol 279 (4) ◽  
pp. H1453-H1459 ◽  
Author(s):  
Lindon H. Young ◽  
Yasuhiko Ikeda ◽  
Rosario Scalia ◽  
Allan M. Lefer
Keyword(s):  
Cardiac Dysfunction ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
C Peptide ◽  
Cardiac Contractile ◽  
No Release ◽  
Cardiac Contractile Dysfunction ◽  
Cardioprotective Effects ◽  
Myocardial Ischemia Reperfusion ◽  
Developed Pressure

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac dysfunction. C-peptide, a cleavage product of proinsulin to insulin processing, induces nitric oxide (NO)-mediated vasodilation. NO is reported to attenuate cardiac dysfunction caused by PMNs after ischemia-reperfusion (I/R). Therefore, we hypothesized that C-peptide could attenuate PMN-induced cardiac dysfunction. We examined the effects of C-peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. C-peptide (70 nmol/kg iv) given 4 or 24 h before I/R significantly improved coronary flow ( P < 0.05), left ventricular developed pressure (LVDP) ( P < 0.01), and the maximal rate of development of LVDP (+dP/d t max) compared with I/R hearts obtained from rats given 0.9% NaCl ( P < 0.01). N G-nitro-l-arginine methyl ester (l-NAME) (50 μmol/l) blocked these cardioprotective effects. In addition, C-peptide significantly reduced cardiac PMN infiltration from 183 ± 24 PMNs/mm2 in untreated hearts to 44 ± 10 and 58 ± 25 PMNs/mm2 in hearts from 4- and 24-h C-peptide-treated rats, respectively. Rat PMN adherence to rat superior mesenteric artery exposed to 2 U/ml thrombin was significantly reduced in rats given C-peptide compared with rats given 0.9% NaCl ( P < 0.001). Moreover, C-peptide enhanced basal NO release from rat aortic segments. These results provide evidence that C-peptide can significantly attenuate PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to I/R at least in part via enhanced NO release.

Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock

1997 ◽  
Vol 273 (2) ◽  
pp. G314-G321 ◽  
Author(s):  
F. Tamion ◽  
V. Richard ◽  
S. Lyoumi ◽  
M. Daveau ◽  
G. Bonmarchand ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Multiorgan Failure ◽  
Endotoxic Shock ◽  
Cytokine Gene Expression ◽  
Tnf Alpha ◽  
Cytokine Gene ◽  
Necrosis Factor Alpha ◽  
Intestinal Ischemia Reperfusion

The intestine plays a major role in the pathophysiology of multiorgan failure. Although the systemic inflammatory response might be induced by endotoxin released through bacterial translocation, other factors such as intestinal ischemia might be implicated. We investigated the relationship between intestinal ischemia-reperfusion and cytokine release in rat models of hemorrhagic or endotoxic shock. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), lactate, and endotoxin, as well as macrophage TNF-alpha and IL-6 mRNA expression, were assessed at the end of shock and resuscitation. Hemodynamic changes and lactate levels suggested the presence of intestinal ischemia in both models. Mesenteric levels of TNF-alpha and IL-6 were increased by hemorrhage and further increased after saline resuscitation. Similar results were obtained with mRNA cytokine gene expression in macrophages. Endotoxin was not detectable in the hemorrhagic group. Endotoxic shock also increased production of cytokines, which, in contrast to hemorrhage, was not further increased by resuscitation. These results suggest that intestinal ischemia-reperfusion upon hemorrhage and resuscitation may be a major trigger for cytokine gene expression in the absence of endotoxin.

Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel

1993 ◽  
Vol 264 (5) ◽  
pp. H1686-H1692 ◽  
Author(s):  
J. W. Horton ◽  
D. J. White
Keyword(s):  
Lipid Peroxidation ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cardiac Contractile Function ◽  
Langendorff Preparation ◽  
Cardiac Contractile ◽  
Intestinal Ischemia Reperfusion

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury

2018 ◽  
Vol 236 (2) ◽  
pp. 69-84 ◽  
Author(s):  
Pongpan Tanajak ◽  
Piangkwan Sa-nguanmoo ◽  
Sivaporn Sivasinprasasn ◽  
Savitree Thummasorn ◽  
Natthaphat Siri-Angkul ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Combined Therapy ◽  
Left Ventricular ◽  
Cardiac Ischemia ◽  
Lv Function ◽  
Insulin Resistant ◽  
Lv Dysfunction ◽  
Dipeptidyl Peptidase 4 Inhibitors

Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) effects on cardiac ischemia/reperfusion (I/R) injury are unclear. Unlike SGLT2-i, dipeptidyl peptidase 4 inhibitors (DPP4-i) have shown effective cardioprotection in cardiac I/R injury. We aimed to investigate whether SGLT2-i reduces myocardial dysfunction and myocardial injury to a greater extent than DPP4-i in obese insulin-resistant rats with/without cardiac I/R injury. The high-fat (HF) diet-induced obese insulin-resistant rats were divided into 4 groups and received the following treatments for 28 days: vehicle (HFV); vildagliptin at a dosage of 3 mg/kg/day (HFVil); dapagliflozin at a dosage of 1 mg/kg/day (HFDa) and combination drugs (HFDaVil). At the end, I/R injury was induced by a 30-min left anterior descending coronary occlusion and 120-min reperfusion. Dapagliflozin showed a greater efficacy than vildagliptin in improving the metabolic impairments, low frequency/high frequency (LF/HF) ratio, systolic blood pressure and left ventricular (LV) function in comparison to HFV rats. In cardiac I/R injury, dapagliflozin had a greater efficacy than vildagiptin in decreasing mitochondrial DRP1, cleaved caspase 3, LV dysfunction and infarct size in comparison to HFV rats. However, the combined therapy showed the greatest efficacy in attenuating LV dysfunction, mitochondrial DRP1 and infarct size in comparison to HFV rats. In conclusion, dapagliflozin has a more pronounced effect than vildagliptin in obese insulin-resistant rats for the improvement of LV function. In rats with cardiac I/R injury, although dapagliflozin had a greater efficacy on cardioprotection than vildagliptin, the combined therapy exerted the highest cardioprotective effects potentially by reducing mitochondrial fission.

Protein kinase C-ζ inhibition exerts cardioprotective effects in ischemia-reperfusion injury

2005 ◽  
Vol 289 (2) ◽  
pp. H898-H907 ◽  
Author(s):  
Aisha Phillipson ◽  
Ellen E. Peterman ◽  
Philip Taormina ◽  
Margaret Harvey ◽  
Richard J. Brue ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Peptide Inhibitor ◽  
Contractile Dysfunction ◽  
Cardiac Contractile ◽  
No Release ◽  
Cardiac Contractile Dysfunction ◽  
Cardioprotective Effects ◽  
Pkc Ζ ◽  
Superoxide Release

Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in marked cardiac contractile dysfunction. A cell-permeable PKC-ζ peptide inhibitor was used to test the hypothesis that PKC-ζ inhibition could attenuate PMN-induced cardiac contractile dysfunction by suppression of superoxide production from PMNs and increase nitric oxide (NO) release from vascular endothelium. The effects of the PKC-ζ peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. The PKC-ζ inhibitor (2.5 or 5 μM, n = 6) significantly attenuated PMN-induced cardiac dysfunction compared with I/R hearts ( n = 6) receiving PMNs alone in left ventricular developed pressure (LVDP) and the maximal rate of LVDP (+dP/d tmax) cardiac function indexes ( P < 0.01), and these cardioprotective effects were blocked by the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (50 μM). Furthermore, the PKC-ζ inhibitor significantly increased endothelial NO release 47 ± 2% (2.5 μM, P < 0.05) and 54 ± 5% (5 μM, P < 0.01) over basal values from the rat aorta and significantly inhibited superoxide release from phorbol-12-myristate-13-acetate-stimulated rat PMNs by 33 ± 12% (2.5 μM) and 40 ± 8% (5 μM) ( P < 0.01). The PKC-ζ inhibitor significantly attenuated PMN infiltration into the myocardium by 46–48 ± 4% ( P < 0.01) at 2.5 and 5 μM, respectively. In conclusion, these results suggest that the PKC-ζ peptide inhibitor attenuates PMN-induced post-I/R cardiac contractile dysfunction by increasing endothelial NO release and by inhibiting superoxide release from PMNs thereby attenuating PMN infiltration into I/R myocardium.

scholarly journals Metformin exerts cardioprotection via attenuating mitochondrial fission in cardiac ischaemia-reperfusion injury in rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Palee ◽  
L Higgins ◽  
T Leech ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Control Group ◽  
Lv Function ◽  
Funding Source ◽  
Cardiac Ischaemia

Abstract Background Cardiac ischemia/reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further cardiomyocytes death and impaired cardiac contractility. Although metformin has been shown to exert cardioprotection in addition to glycemic control, its effect on cardiac I/R injury are still controversy, and the comparative doses of metformin in cardiac I/R injury have never been investigated. Purpose We hypothesized that metformin given acutely prior to cardiac ischaemia exerts cardioprotection in rats with cardiac I/R injury via attenuating cardiac mitochondrial dysfunction, leading to improved left ventricular (LV) function. Methods Forty Male Wistar rats were subjected to cardiac I/R injury. Four treatment groups were investigated. The first group received saline as a control group. The second to the fourth groups received metformin at 100, 200, and 400 mg/kg intravenously, respectively. During the I/R protocols, the LV function, arrhythmia score, and mortality rate were determined. At the end, the hearts were rapidly removed to determine infarct size, cardiac mitochondrial function, cardiac mitochondrial dynamics, and cardiac apoptosis. Results Metformin 200 mg/kg exerted the highest level of cardioprotection through the attenuated incidence of arrhythmia, decreased infarct size (Fig. 1), improved cardiac mitochondrial function, and decreased mitochondrial fission (Fig. 1) and cardiac apoptotic markers, leading to improved cardiac function during I/R injury. Although Metformin at all doses effectively decreased infarct size, improved cardiac mitochondrial function and LV function, Metformin at 200 mg/kg exerted the best efficacy (Fig. 1). Conclusions Metformin exerts cardioprotection by attenuating mitochondrial dysfunction and decreased mitochondrial fission, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings also indicate the potential biphasic effects of metformin on infarct size which are dose-dependent. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency Thailand (NC), and Thailand Research Fund (SCC)

Abstract 3894: Inhibition of iNOS Uncoupling by Tetrahydrobiopterin Confers Cardioprotection through Protein S- Nitrosylation in Streptozotocin-Induced Diabetic Rat

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Toru Okazaki ◽  
Hajime Otani ◽  
Koji Yamashita ◽  
Hiromi Jo ◽  
Kei Yoshioka ◽  
...  
Keyword(s):  
Infarct Size ◽  
Rat Heart ◽  
Ischemia Reperfusion ◽  
Protein S ◽  
Left Ventricular ◽  
Isolated Rat Heart ◽  
Diabetic Rat ◽  
Lv Function ◽  
Oxide Synthase

Although expression of inducible nitric oxide synthase (iNOS) and oxidative stress are increased in diabetic (DM) hearts, the role of iNOS uncoupling in ischemia/reperfusion (IR) injury remains unknown. Because iNOS-derived NO is known to play a crucial role in cardioprotection against IR injury in non-DM hearts, we hypothesized that iNOS uncoupling may compromise tolerance to IR injury in the DM heart by decreasing the bioavailability of NO. The expression and activity of iNOS but not n/eNOS were increased in the streptozotocin-induced DM rat heart. Under Langendorff perfusion, superoxide generation as evaluated by dihydroethidium accumulation in the nucleus was significantly increased in cardiomyocytes of the DM heart, but it was inhibited by treatment with the NOS co-factor tetrahydrobiopterin (BH4; 10 μM) or an iNOS selective inhibitor 1400W (10 μM). BH4 increased NOx, a marker of NO bioavailability, and cGMP in the DM heart. The increase in cGMP by BH4 was abrogated by co-treatment with 1400W or a NO-sensitive guanylyl cyclase inhibitor ODQ (10 μM). BH4 significantly decreased nitrotyrosin formation but increased protein S -nitrosylation in the DM heart. The increase in protein S -nitrosylation by BH4 was abolished by co-treatment with a thiol reducing agent dithiothreitol (DTT; 5 mM). The isolated rat heart was subjected to 30 min global ischemia followed by 120 min reperfusion. Post-ischemic recovery of left ventricular (LV) function and infarct size was comparable between the non-DM and the DM hearts. Pre-ischemic treatment with BH4 significantly improved post-ischemic LV function and reduced infarct size only in the DM heart. Co-treatment with BH4 and 1400W, ODQ, or DTT had no significant effect on post-ischemic LV function and infarct size in the non-DM heart. However, co-treatment with BH4 and 1400W or DTT but not ODQ abolished BH4-induced improvement of post-ischemic LV function and reduction of infarct size in the DM heart. These results suggest that inhibition of iNOS uncoupling by BH4 confers cardioprotection against IR injury in the streptozotocin-induced DM rat heart by increasing the bioavailability of NO and this cardioprotective effect is mediated by protein S -nitrosylation but not cGMP.

scholarly journals PKCβ modulates ischemia-reperfusion injury in the heart

2008 ◽  
Vol 294 (4) ◽  
pp. H1862-H1870 ◽  
Author(s):  
Linghua Kong ◽  
Martin Andrassy ◽  
Jong Sun Chang ◽  
Chun Huang ◽  
Tomohiro Asai ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Enhanced Recovery ◽  
Ischemia Reperfusion ◽  
Homozygous Deletion ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Lv Function ◽  
Wild Type

Protein kinase C-βII (PKCβII) is an important modulator of cellular stress responses. To test the hypothesis that PKCβII modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKCβ-null (PKCβ−/−) and wild-type mice fed the PKCβ inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKCβII in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKCβ protected ischemic myocardium. Homozygous deletion of PKCβ significantly diminished phosphorylation of c-Jun NH2-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKCβ in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCβ may represent a potent strategy to protect the vulnerable myocardium.

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