Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction

2000 ◽  
Vol 279 (2) ◽  
pp. R666-R676 ◽  
Author(s):  
Richard A. Hopper ◽  
Christopher R. Forrest ◽  
Huai Xu ◽  
Anguo Zhong ◽  
Wei He ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Muscle Blood Flow ◽  
Signal Transduction Pathway ◽  
Muscle Flap ◽  
Polymyxin B ◽  
Myeloperoxidase Activity ◽  
Muscle Flaps ◽  
Arterial Blood

Protein kinase C (PKC) inhibitors, chelerythrine (Chel, 0.6 mg) and polymyxin B (Poly B, 1.0 mg), and PKC activators, phorbol 12-myristate 13-acetate (PMA, 0.05 mg) and 1-oleoyl-2-acetyl glycerol (OAG, 0.1 mg), were used as probes to investigate the role of PKC in mediation of ischemic preconditioning (IPC) of noncontracting pig latissimus dorsi (LD) muscles against infarction in vivo. These drugs were delivered to each LD muscle flap (8 × 12 cm) by 10 min of local intra-arterial infusion. It was observed that LD muscle flaps sustained 43 ± 5% infarction when subjected to 4 h of global ischemia and 24 h of reperfusion. IPC with three cycles of 10 min ischemia-reperfusion reduced muscle infarction to 25 ± 3% ( P < 0.05). This anti-infarction effect of IPC was blocked by Chel (42 ± 7%) and Poly B (37 ± 2%) and mimicked by PMA (19 ± 10%) and OAG (14 ± 5%) treatments ( P < 0.05), given 10 min before 4 h of ischemia. In addition, the ATP-sensitive K+ (KATP) channel antagonist sodium 5-hydroxydecanoate attenuated ( P < 0.05) the anti-infarction effect of IPC (37 ± 2%), PMA (44 ± 17%), and OAG (46 ± 9%). IPC, OAG, and Chel treatment alone did not affect mean arterial blood pressure or muscle blood flow assessed by 15-μm radioactive microspheres. Western blot analysis of muscle biopsies obtained before (baseline) and after IPC demonstrated seven cytosol-associated isoforms, with nPKCɛ alone demonstrating progressive cytosol-to-membrane translocation within 10 min after the final ischemia period of IPC. Using differential fractionation, it was observed that nPKCɛ translocated to a membrane compartment other than the sarcolemma and/or sarcoplasmic reticulum. Furthermore, IPC and preischemic OAG but not postischemic OAG treatment reduced ( P < 0.05) muscle myeloperoxidase activity compared with time-matched ischemic controls during 16 h of reperfusion after 4 h of ischemia. Taken together, these observations indicate that PKC plays a central role in the anti-infarction effect of IPC in pig LD muscles, most likely through a PKC-KATPchannel-linked signal-transduction pathway.

Role of ATP-sensitive K+ channels in ischemic preconditioning of skeletal muscle against infarction

1997 ◽  
Vol 273 (1) ◽  
pp. H44-H51 ◽  
Author(s):  
C. Y. Pang ◽  
P. Neligan ◽  
H. Xu ◽  
W. He ◽  
A. Zhong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Energy Charge ◽  
Katp Channels ◽  
High Energy ◽  
Intraarterial Infusion ◽  
Muscle Flaps ◽  
Charge Potential

We studied the role and mechanism of ATP-sensitive K+ (KATP) channels in ischemic preconditioning (IPC) of skeletal muscle against infarction in vivo. Surgically denervated, noncontractile latissimus dorsi muscle flaps in pentobarbitone-anesthetized pigs were assigned to nine groups: control; IPC (3 cycles of 10-min ischemia/reperfusion); preischemic lemakalim (LMK, 0.18 mg/muscle); postischemic LMK; sodium 5-hydroxydecanoate (5-HD, 27 mg/muscle) before IPC; glibenclamide (Glib 0.3 mg/kg iv) before IPC; 5-HD before preischemic LMK; 5-HD before ischemia; and Glib before ischemia. Except for Glib, all drugs were delivered to each muscle by 10-min local intraarterial infusion to avoid systemic effects. All muscle flaps underwent 4 h of global ischemia. Infarction was assessed at 48 h of reperfusion. In a separate study, muscle biopsies were taken before, during, and after ischemia for assay of high-energy phosphate and lactate contents and myeloperoxidase (MPO) activity. It was observed that muscle infarction in the IPC (24 +/- 2%) and preischemic LMK (21 +/- 2%) groups were smaller (P < 0.05) than that in the control (42 +/- 2%). The anti-infarction effect of IPC and LMK was blocked by 5-HD or Glib. IPC and preischemic LMK caused a higher (P < 0.05) muscle content of ATP and energy charge potential, a lower (P < 0.05) muscle content of lactate during ischemia, and a lower (P < 0.05) muscle MPO activity throughout 16 h of reperfusion compared with the control. These observations indicated for the first time that KATP channels are also involved in the anti-infarction effect of IPC in noncontractile skeletal muscle in vivo. Presently, the cause and importance of energy-sparing and neutrophil-inhibitory effects of IPC and LMK are not known.

scholarly journals Ischemic Preconditioning Prevents Endothelial Injury and Systemic Neutrophil Activation During Ischemia-Reperfusion in Humans In Vivo

Circulation ◽  
2001 ◽  
Vol 103 (12) ◽  
pp. 1624-1630 ◽  
Author(s):  
Rajesh K. Kharbanda ◽  
Mark Peters ◽  
Benjamin Walton ◽  
Mia Kattenhorn ◽  
Michael Mullen ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Neutrophil Activation ◽  
Endothelial Injury

scholarly journals Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo

2004 ◽  
Vol 286 (5) ◽  
pp. H1649-H1653 ◽  
Author(s):  
Yiru Guo ◽  
Adam B. Stein ◽  
Wen-Jian Wu ◽  
Wei Tan ◽  
Xiaoping Zhu ◽  
...  
Keyword(s):  
At Risk ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Effective Means ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Water Soluble ◽  
Arterial Blood

Although carbon monoxide (CO) has traditionally been viewed as a toxic gas, increasing evidence suggests that it plays an important homeostatic and cytoprotective role. Its therapeutic use, however, is limited by the side effects associated with CO inhalation. Recently, transition metal carbonyls have been shown to be a safe and effective means of transporting and releasing CO groups in vivo. The goal of the present study was to test whether a water-soluble CO-releasing molecule, tricarbonylchloro(glycinato) ruthenium (II) (CORM-3), reduces infarct size in vivo when given in a clinically relevant manner, i.e., at the time of reperfusion. Mice were subjected to a 30-min coronary artery occlusion followed by 24 h of reperfusion and were given either CORM-3 (3.54 mg/kg as a 60-min intravenous infusion starting 5 min before reperfusion) or equivalent doses of inactive CORM-3, which does not release CO. CORM-3 had no effect on arterial blood pressure or heart rate. The region at risk did not differ in control and treated mice (44.5 ± 3.5% vs. 36.5 ± 1.6% of the left ventricle, respectively). However, infarct size was significantly smaller in treated mice [25.8 ± 4.9% of the region at risk ( n = 13) vs. 47.7 ± 3.8% ( n = 14), P < 0.05]. CORM-3 did not increase carboxyhemoglobin levels in the blood. These results suggest that a novel class of drugs, CO-releasing molecules, can be useful to limit myocardial ischemia-reperfusion injury in vivo.

CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

2014 ◽  
Vol 307 (7) ◽  
pp. F783-F797 ◽  
Author(s):  
A. Zuk ◽  
M. Gershenovich ◽  
Y. Ivanova ◽  
R. T. MacFarland ◽  
S. P. Fricker ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Myeloperoxidase Activity ◽  
Long Term Effects ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Before And After

We examined whether antagonism of the CXCR4 receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR4 is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR4 antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR4 inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR4 antagonism with plerixafor may be a potential option to prevent AKI.

A comparison of skin and muscle for cortical revascularization

2000 ◽  
Vol 13 (03) ◽  
pp. 128-134 ◽  
Author(s):  
J. D. Fowler ◽  
G. G. Matte ◽  
G. H. Johnston ◽  
C. D. Porter
Keyword(s):  
Blood Flow ◽  
Soft Tissue ◽  
Cortical Bone ◽  
Blood Supply ◽  
Muscle Blood Flow ◽  
Muscle Flap ◽  
Trapezius Muscle ◽  
Random Pattern ◽  
Bone Blood Flow ◽  
Muscle Flaps

SummaryThe purpose of this project was to compare the ability of skin and muscle to revascularize cortical bone segments in the canine distal limb. A model mimicking severe combined soft tissue and orthopaedic injury with bone devascularization involving the canine metatarsus was developed. Soft tissue defects were reconstructed with a reverse saphenous conduit flap or a free trapezius muscle flap. Cortical bone blood flow was determined by the radiolabeled microsphere method at 21 days post-reconstruction. In addition cortical porosity, the amount of fluorescent labelled intracortical new bone, and the maximum depth of periosteal new bone were determined. Significant differences were not detected between skin and muscle reconstructions for any of the measured parameters of cortical revascularization. The mean values for cortical bone blood flow were higher than expected from previous studies, and did not correlate with subjective assessments of adhesion quality between bone and reconstructive tissue onlay. The reverse saphenous conduit flap, and the free trapezius muscle flap, may respectively provide superior blood supply to underlying bone than local random pattern skin and local pedicled muscle. The reverse saphenous conduit flap has a robust and reliable vascular supply, unlike that to random pattern skin. The free transfer of muscle maintains a vigorous blood supply, and has shown improvements in blood flow over pedicled muscle. Blood flow to both tissue types may be favourably affected by the denervation associated with transfer, causing arteriolar vasodilation and reductions in vascular resistance. In this model, comparable revascularization of cortical bone at 21 days was seen beneath reverse saphenous conduit flaps and free trapezius muscle flaps. However, a role for endosteal revascularization cannot be excluded.Cortical revascularization by skin and muscle reconstruction was compared at 21 days in a canine metatarsal model. Significant differences in cortical bone blood flow were not detected

Abstract 411: Endogenous miRNA Induced By Ischemic Preconditioning Reduces Myocardial Infarct Size following Ischemia/Reperfusion In Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Chang Yin ◽  
Fadi N Salloum ◽  
Rakesh C Kukreja
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Coronary Artery Ligation ◽  
Myocardial Infarct Size ◽  
Artery Ligation ◽  
Buffer Control

BACKGROUND: Due to its short length (~24 nt) and non-coding nature, microRNA (miRNA) used to be regarded as “evolutionary transcriptional debris”. Recent evidence suggests that miRNA is a novel regulator for transcription and translation. It is known that brief episodes of ischemia during ischemic preconditioning (IPC) trigger complex genetic pro-survival program that results in modulation of several key proteins involved in protection against I/R injury. We hypothesized that miRNA synthesized during IPC is the potential mediator of such protection. METHODS / RESULTS : Hearts were isolated from 3 groups (n = 6/group) of adult ICR mice and subjected to the following treatments in Langendorff mode: 120 min of perfusion with Krebs-Henseleit buffer (control); 30 min global ischemia followed by 1 hr reperfusion (I/R); 2 cycles of 30 sec ischemia and 90 sec reperfusion followed by 30 min ischemia and 1 hr reperfusion (IPC). Infarct size (IS) was measured by triphenyl tetrazolium staining. IPC in the Langendorff model reduced IS from 29.7 ± 2.1% in the I/R hearts to 9.1 ± 1.8 % in the IPC group. This protection was associated with a significant induction of miRNA-1 (162 ± 13%), miRNA-21 (118 ± 6%), and miRNA-24 (46 ± 12%). To test its protective role, miRNA was extracted from 6 hearts following the IPC protocol; and then injected in vivo into the left ventricle wall in another group of 6 mice. Forty-eight hrs later, these mice were subjected to I/R injury in vivo by left coronary artery ligation for 30 min followed by reperfusion for 24 hr. In addition, a subset of mice was treated with miRNA inhibitors (methylated antisense miRNA) in conjunction with miRNA from IPC hearts. The results show that miRNA extracted from the IPC hearts reproduced a protective phenotype with significantly lower infarction (18.8 ± 2.5 %) in vivo as compared to saline-treated control (37.5 ± 2.2%). This protective effect was totally abolished by specific inhibitors of miRNA-1 and miRNA-21 (IS: 43.7 ± 2.1%). CONCLUSION : miRNA extracted from preconditioned hearts shows a protective role against I/R injury. The detection of miRNA in preconditioned hearts offers a novel strategy in cardioprotection. Further studies are needed to identify the gene targets by which miRNA generate protective phenotype.

Abstract 13914: Ischemic Preconditioning Induces MG53 Secretion From the Heart Through H 2 O 2 /PKC-delta Signaling

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dan Shan ◽  
Yan Zhang ◽  
Rui-ping Xiao
Keyword(s):  
Ischemic Preconditioning ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Embryonic Stem ◽  
Underlying Mechanism ◽  
Neonatal Rat ◽  
Control Group ◽  
Systemic Delivery

Introduction: Ischemic heart disease is the leading cause of morbidity and mortality worldwide. Ischemic preconditioning (IPC) is the most powerful intrinsic protection against cardiac ischemia/reperfusion (I/R) injury. Previous studies have shown that a multifunctional TRIM family protein, MG53 (or TRIM72), not only plays an essential role in IPC-mediated cardioprotection, but also as a myokine/cardiokine, can be secreted from the heart and skeletal muscle in response to metabolic stress in addition to its intracellular actions. Hypothesis: We hypothesized that IPC-mediated cardioprotection is causally related to MG53 secretion and figured out the underlying mechanism. Methods and Results: Using proteomic analysis in conjunction with genetic and pharmacological approaches, we examined MG53 secretion in response to IPC and explored the underlying mechanism using rodents in in vivo , isolated perfused hearts, and cultured neonatal rat ventricular cardiomyocytes. IPC profoundly increased perfusate MG53 levels in mouse hearts by 5.50 ± 0.32 and 4.26 ± 0.40 folds from baseline over 0-60 and 60-120 min of reperfusion, respectively. Mechanistically, IPC-induced MG53 secretion is dependent on H 2 O 2 -evoked, Src-mediated phosphorylation of PKC-δ-Y311. Functionally, systemic delivery of recombinant human MG53 proteins (rhMG53) to mimic elevated circulating MG53 not only restored IPC function in MG53-deficient mice, but also protected rodent hearts from I/R injury even in the absence of IPC. Treatment of rhMG53 overtly decreased the infarct size (IF/AAR) induced by I/R compared to the BSA-treated control group (11.9 ± 1.8% vs 27.3 ± 2.0%, P <0.01), and reduced the mortality from 44.7% to 5.3% in rats. Moreover, H 2 O 2 augmented MG53 secretion, and MG53 knockdown exacerbated H 2 O 2 -induced cell injury in human embryonic stem cell-derived cardiomyocytes. Conclusions: In conclusion, IPC and oxidative stress can trigger MG53 secretion from the heart via an H 2 O 2 -PKC-δ-dependent mechanism, and secreted MG53 acts as an essential factor conveying IPC-induced cardioprotection against ischemia/reperfusion injury. Recombinant MG53 proteins can be developed into a novel treatment for various diseases of human heart in which the endogenous MG53 is low.

Ceramide in the antiapoptotic effect of ischemic preconditioning

2004 ◽  
Vol 286 (1) ◽  
pp. H246-H251 ◽  
Author(s):  
Laurent Argaud ◽  
Annie-France Prigent ◽  
Lara Chalabreysse ◽  
Joseph Loufouat ◽  
Michel Lagarde ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Kinase Assay ◽  
Control Group ◽  
Blue Dye ◽  
Triphenyltetrazolium Chloride ◽  
Antiapoptotic Effect ◽  
Ceramide Production

Although the mechanism by which ischemic preconditioning (PC) inhibits myocardial apoptosis during ischemia-reperfusion is unclear, evidence indicates a role for the secondary messenger ceramide. We investigated in vivo whether PC may affect ceramide and sn-1,2-diacylglycerol (DAG) production, and attenuate apoptosis during ischemia. Rabbits underwent 30 min of ischemia, followed by 4 h of reperfusion. Before this, they received either no intervention (control group) or one episode of 5 min of ischemia, followed by 5 min of reperfusion (PC group), or an intravenous administration of the sphingomyelinase inhibitor D609. Myocardial content of ceramide and DAG was measured using the DAG kinase assay at different time points of the experiment. Apoptosis was detected and quantified by a sandwich enzyme immunoassay. Both AR and infarct size were measured using blue dye injection and triphenyltetrazolium chloride staining. Control hearts exhibited a peak of ceramide production at 5 min of the prolonged ischemia, with a mean value averaging 64 ± 5 ng/mg tissue ( P < 0.05 vs. 48 ± 4 ng/mg at baseline). In contrast, ischemic PC and D609 prevented ceramide increase during the prolonged ischemia. Myocardial DAG content was increased only in PC hearts at 30 min of ischemia. Preconditioned and D609 groups developed less apoptosis, as well as a limited infarct size, compared with the control group. These results suggest that the antiapoptotic effect of PC may be due to a reduced ceramide production during sustained ischemia in the rabbit heart.

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