Differential Role of Pim-1 Kinase in Anesthetic-induced and Ischemic Preconditioning against Myocardial Infarction

Background Ischemic preconditioning (IPC) and anesthetic-induced preconditioning against myocardial infarction are mediated via protein kinase B. Pim-1 kinase acts downstream of protein kinase B and was recently shown to regulate cardiomyocyte survival. The authors tested the hypothesis that IPC and anesthetic-induced preconditioning are mediated by Pim-1 kinase. Methods Pentobarbital-anesthetized male C57Black/6 mice were subjected to 45 min of coronary artery occlusion and 3 h of reperfusion. Animals received no intervention, Pim-1 kinase inhibitor II (10 microg/g intraperitoneally), its vehicle dimethyl sulfoxide (10 microl/g intraperitoneally), or 1.0 minimum alveolar concentration desflurane alone or in combination with Pim-1 kinase inhibitor II (10 microg/g intraperitoneally). IPC was induced by three cycles of 5 min ischemia-reperfusion each, and animals received IPC either alone or in combination with Pim-1 kinase inhibitor II (10 microg/g intraperitoneally). Infarct size was determined with triphenyltetrazolium chloride, and area at risk was determined with Evans blue (Sigma-Aldrich, Taufkirchen, Germany). Protein expression of Pim-1 kinase, Bad, phospho-Bad, and cytosolic content of cytochrome c were measured using Western immunoblotting. Results Infarct size in the control group was 47 + or - 2%. Pim-1 kinase inhibitor II (44 + or - 2%) had no effect on infarct size. Desflurane (17 + or - 3%) and IPC (19 + or - 2%) significantly reduced infarct size compared with control (both P < 0.05 vs. control). Blockade of Pim-1 kinase completely abrogated desflurane-induced preconditioning (43 + or - 3%), whereas IPC (35 + or - 3%) was blocked partially. Desflurane tended to reduce cytosolic content of cytochrome c, which was abrogated by Pim-1 kinase inhibitor II. Conclusion These data suggest that Pim-1 kinase mediates at least in part desflurane-induced preconditioning and IPC against myocardial infarction in mice.

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Modification of ischemia/reperfusion induced infarct size by ischemic preconditioning in hypertrophied hearts

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0400 ◽

2021 ◽

Vol 99 (2) ◽

pp. 218-223

Author(s):

Mohamad Nusier ◽

Mohammad Alqudah ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Protein Kinase ◽

Cardiac Hypertrophy ◽

Infarct Size ◽

P38 Mapk ◽

Ischemic Preconditioning ◽

Creatine Phosphokinase ◽

Ischemia Reperfusion ◽

Mitogen Activated Protein Kinase ◽

Normal Heart ◽

Mitogen Activated Protein

This study examined the effects of ischemic preconditioning (IP) on the ischemia/reperfusion (I/R) induced injury in normal and hypertrophied hearts. Cardiac hypertrophy in rabbits was induced by L-thyroxine (0.5 mg/kg/day for 16 days). Hearts with or without IP (3 cycles of 5 min ischemia and 10 min reperfusion) were subjected to I/R (60 min ischemia followed by 60 min reperfusion). IP reduced the I/R-induced infarct size from 68% to 24% and 57% to 33% in the normal and hypertrophied hearts, respectively. Leakage of creatine phosphokinase in the perfusate from the hypertrophied hearts due to I/R was markedly less than that form the normal hearts; IP prevented these changes. Although IP augmented the increase in phosphorylated p38-mitogen-activated protein kinase (p38-MAPK) content due to I/R, this effect was less in the hypertrophied than in the normal heart. These results suggest that reduced cardioprotection by IP of the I/R-induced injury in hypertrophied hearts may be due to reduced activation of p38-MAPK in comparison with normal hearts.

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Ischemic preconditioning in rats: role of mitochondrial KATP channel in preservation of mitochondrial function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.1.h305 ◽

2000 ◽

Vol 278 (1) ◽

pp. H305-H312 ◽

Cited By ~ 128

Author(s):

Ryan M. Fryer ◽

Janis T. Eells ◽

Anna K. Hsu ◽

Michele M. Henry ◽

Garrett J. Gross

Keyword(s):

Infarct Size ◽

Ischemic Preconditioning ◽

Mitochondrial Function ◽

Ischemia Reperfusion ◽

Mitochondrial Protein ◽

Atp Synthesis ◽

Area At Risk ◽

Selective Antagonist ◽

Mitochondrial Katp Channel

We examined the role of the sarcolemmal and mitochondrial KATPchannels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 ± 1%) versus control (56 ± 1%). The sarcolemmal KATP channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial KATP channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 ± 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 ± 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 ± 0.30 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 ± 0.06 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. IPC significantly increased ATP synthesis to 1.86 ± 0.23 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1. However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 ± 0.15 μmol ⋅ min−1 ⋅ mg mitochondrial protein−1). These data are consistent with the notion that inhibition of mitochondrial KATPchannels attenuates IPC by reducing IPC-induced protection of mitochondrial function.

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Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of δ-opioid receptor

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01143.2003 ◽

2004 ◽

Vol 287 (4) ◽

pp. H1786-H1791 ◽

Cited By ~ 42

Author(s):

Shinji Okubo ◽

Yujirou Tanabe ◽

Kenji Takeda ◽

Michihiko Kitayama ◽

Seiyu Kanemitsu ◽

...

Keyword(s):

Infarct Size ◽

Opioid Receptor ◽

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Terminal Deoxynucleotidyl Transferase ◽

Control Group ◽

Apoptotic Cells ◽

Protective Effects ◽

Δ Opioid Receptor

We examined whether ischemic preconditioning (IPC) attenuates ischemia-reperfusion injury, in part, by decreasing apoptosis and whether the δ-opioid receptor (DOR) plays a pivotal role in the regulation of apoptosis. Rabbits were subjected to 30-min coronary artery occlusion (CAO) and 180 min of reperfusion. IPC was elicited with four cycles of 5-min ischemia and 10-min reperfusion before CAO. Morphine (0.3 mg/kg iv) was given 15 min before CAO. Naloxone (Nal; 10 mg/kg iv) and naltrindole (Nti; 10 mg/kg iv), the respective nonselective and selective DOR antagonists were given 10 min before either morphine or IPC. Infarct size (%risk area) was reduced from 46 ± 3.8 in control to 11.6 ± 1.0 in IPC and 19.5 ± 3.8 in the morphine group (means ± SE; P < 0.001 vs. control). Nal blocked the protective effects of IPC and morphine, as shown by the increase in infarct size to 38.6 ± 7.2 and 44.5 ± 1.8, respectively. Similarly, Nti blocked IPC and morphine-induced protection. The percentage of apoptotic cells (revealed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) decreased in IPC (3.6 ± 1.9) and morphine groups (5.2 ± 1.2) compared with control group (12.4 ± 1.6; P < 0.001). Nti pretreatment increased apoptotic cells 11.2 ± 2.2% in IPC and 12.1 ± 0.8% in morphine groups. Nal failed to block inhibition of apoptosis in the IPC group (% of cells: 5.7 ± 1.3 vs. 3.6 ± 1.9 in IPC alone; P > 0.05). These results were also confirmed by nucleosomal DNA laddering pattern. We conclude that IPC reduces lethal injury, in part, by decreasing apoptosis after ischemia-reperfusion and activation of the DOR may play a crucial role in IPC or morphine-induced myocardial protection.

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Remifentanil Preconditioning Confers Cardioprotection via Cardiac κ- and δ-Opioid Receptors

Anesthesiology ◽

10.1097/00000542-200502000-00020 ◽

2005 ◽

Vol 102 (2) ◽

pp. 371-378 ◽

Cited By ~ 64

Author(s):

Ye Zhang ◽

Michael G. Irwin ◽

Tak Ming Wong ◽

Mai Chen ◽

Chun-Mei Cao

Keyword(s):

At Risk ◽

Protein Kinase C ◽

Protein Kinase ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Katp Channel ◽

Area At Risk ◽

Mitochondrial Katp Channel ◽

Ringer’S Solution ◽

Kinase C

Background Remifentanil preconditioning (RPC) reduces the infarct size in anesthetized rat hearts, and this effect seems to be mediated by all three types of opioid receptors (ORs). Because there is evidence of only kappa- and delta- but not mu-ORs in the rat heart, the authors investigated whether RPC confers cardioprotection via cardiac kappa- and delta-OR as well as via extracardiac mu-OR agonist activity. The authors also investigated the involvement of signaling mechanisms, namely protein kinase C and mitochondrial adenosine triphosphate-sensitive potassium (KATP) channels. Methods The hearts of male Sprague-Dawley rats weighing 190-210 g were removed, mounted on a Langendorff apparatus, and perfused retrogradely at 100 cm H2O with Krebs-Ringer's solution. All hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The study consisted of three series of experiments on the effect of ischemic preconditioning or RPC (10, 50, and 100 ng/ml remifentanil) after blockade of OR subtypes (delta-OR antagonist naltrindol, kappa-OR antagonist nor-binaltorphimine, and mu-OR antagonist CTOP). The involvement of protein kinase C or the KATP channel in the cardioprotection of RPC was also investigated using specific blockers in each group. RPC was produced by three cycles of 5-min perfusion of remifentanil in Krebs-Ringer's solution interspersed with a 5-min reperfusion with Krebs solution only. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Results Infarct size as a percentage of the area at risk was significantly reduced after RPC from 51.9 +/- 5.0% (control, n = 8) to 36.2 +/- 10.0% (100 ng/ml RPC, n = 8, P < 0.01). This effect was stopped by pretreatment with naltrindol (52.3 +/- 5.2%) and nor-binaltorphimine (43.5 +/- 6.0%) but not CTOP (37.1 +/- 6.0%). Chelerythrine and GF109203X, both protein kinase C inhibitors, abolished the effects of RPC or ischemic preconditioning on infarct size as a percentage of area at risk. 5-Hydroxydecanoate (a selective mitochondrial KATP channel blocker) also abolished the cardioprotection of RPC and IPC, but HMR-1098 (a selective inhibitor of the sarcolemmal KATP channel) did not. Conclusion Cardiac delta- and kappa- but not mu-ORs mediate the cardioprotection produced by RPC. Both protein kinase C and the mitochondrial KATP channel were involved in this effect.

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Comparative Effects of Verapamil, Nicardipine, and Nitroglycerin on Myocardial Ischemia/Reperfusion Injury

Anesthesiology Research and Practice ◽

10.1155/2011/521084 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Hitoshi Yui ◽

Uno Imaizumi ◽

Hisashi Beppu ◽

Mitsuhiro Ito ◽

Munetaka Furuya ◽

...

Keyword(s):

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Rabbit Model ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Control Group ◽

Area At Risk ◽

Group A

The aim of this experiment was to establish whether verapamil, nicardipine, and nitroglycerin have (1) infarct size-limiting effects and (2) antiarrhythmic effects inin vivorabbit hearts during ischemia/reperfusion. Rabbits received regional ischemia by 30 min of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion under ketamine and xylazine anesthesia. The animals were randomly assigned to the following 4 treatment groups: a control group, a verapamil group, a nicardipine group, and a nitroglycerin group. A continuous infusion of verapamil, nicardipine, or nitroglycerin was initiated 5 min prior to ischemia. Infarct size/area at risk decreased in verapamil, and nitroglycerin. The incidence of ischemia-induced arrhythmia decreased in nicardipine, verapamil and nitroglycerin. The incidence of reperfusion-induced arrhythmias decreased in verapamil and nitroglycerin. From the present experimental results, verapamil and nitroglycerin rather than nicardipine did afford significant protection to the heart subjected to ischemia and reperfusion in a rabbit model.

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Adrenomedullin gene delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00270.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. H1506-H1514 ◽

Cited By ~ 83

Author(s):

Kazuo Kato ◽

Hang Yin ◽

Jun Agata ◽

Hideaki Yoshida ◽

Lee Chao ◽

...

Keyword(s):

Myocardial Infarction ◽

Gene Transfer ◽

Gene Delivery ◽

Infarct Size ◽

P38 Mapk ◽

Ischemia Reperfusion ◽

Terminal Deoxynucleotidyl Transferase ◽

Area At Risk ◽

Calcitonin Gene ◽

Myocardial Ischemia Reperfusion

Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia-reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide [CGRP(8–37)]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the Akt-Bad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.

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Preconditioning protects the heart in a prolonged uremic condition

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00379.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. H1229-H1236 ◽

Cited By ~ 30

Author(s):

Gabriella F. Kocsis ◽

Márta Sárközy ◽

Péter Bencsik ◽

Márton Pipicz ◽

Zoltán V. Varga ◽

...

Keyword(s):

Infarct Size ◽

Ischemic Preconditioning ◽

Metabolic Diseases ◽

Ischemia Reperfusion Injury ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Cardioprotective Effect ◽

Area At Risk ◽

Protein Levels ◽

Male Wistar Rats

Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wistar rats. The development of uremia was verified 29 wk after surgery. Transthoracic echocardiography was performed to monitor cardiac function. At week 30, hearts of nephrectomized and sham-operated rats were isolated and subjected to a 30-min coronary occlusion followed by 120 min reperfusion with or without preceding preconditioning induced by three intermittent cycles of brief ischemia and reperfusion. In nephrectomized rats, plasma uric acid, carbamide, and creatinine as well as urine protein levels were increased as compared with sham-operated controls. Systolic anterior and septal wall thicknesses were increased in nephrectomized rats, suggesting the development of a minimal cardiac hypertrophy. Ejection fraction was decreased and isovolumic relaxation time was shortened in nephrectomized rats demonstrating a mild systolic and diastolic dysfunction. Infarct size was not affected significantly by nephrectomy itself. Ischemic preconditioning significantly decreased infarct size from 24.8 ± 5.2% to 6.6 ± 1.3% in the sham-operated group and also in the uremic group from 35.4 ± 9.5% to 11.9 ± 3.1% of the area at risk. Plasma ANG II and nitrotyrosine were significantly increased in the uremic rats. We conclude that although prolonged experimental uremia leads to severe metabolic changes and the development of a mild myocardial dysfunction, the cardioprotective effect of ischemic preconditioning is still preserved.

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Ceramide in the antiapoptotic effect of ischemic preconditioning

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00638.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. H246-H251 ◽

Cited By ~ 41

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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Speckle tracking imaging improves in vivo assessment of EPO-induced myocardial salvage early after ischemia-reperfusion in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01058.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. H1679-H1686 ◽

Cited By ~ 13

Author(s):

Frederic Treguer ◽

Erwan Donal ◽

Sophie Tamareille ◽

Nehmat Ghaboura ◽

Geneviève Derumeaux ◽

...

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Rat Model ◽

Speckle Tracking ◽

Ischemia Reperfusion ◽

Control Group ◽

Myocardial Salvage ◽

Speckle Tracking Imaging ◽

Triphenyltetrazolium Chloride ◽

Conventional Echocardiography

A noninvasive assessment of infarct size and transmural extension of myocardial infarction (TEMI) is fundamental in experimental models of ischemia-reperfusion. Conventional echocardiography parameters are limited in this purpose. This study was designed to examine whether speckle tracking imaging can be used in a rat model of ischemia-reperfusion to accurately detect the reduction of infarct size and TEMI induced by erythropoietin (EPO) as early as 24 h after reperfusion. Rats were randomly assigned to one of three groups: myocardial infarction (MI)-control group, 45 min ischemia followed by 24 h of reperfusion; MI-EPO group, similar surgery with a single bolus of EPO administered at the onset of reperfusion; and sham-operated group. Short-axis two-dimensional echocardiography was performed after reperfusion. Global radial (GSr) and circumferential (GScir) strains were compared with infarct size and TEMI assessed after triphenyltetrazolium chloride staining. As a result, ejection fraction, shortening fraction, GSr, and GScir significantly correlated to infarct size, whereas only GSr and GScir significantly correlated to TEMI. EPO significantly decreased infarct size (30.8 ± 3.5 vs. 56.2 ± 5.7% in MI-control, P < 0.001) and TEMI (0.37 ± 0.05 vs. 0.77 ± 0.05 in MI-control, P < 0.001). None of the conventional echocardiography parameters was significantly different between the MI-EPO and MI-control groups, whereas GSr was significantly higher in the MI-EPO group (29.1 ± 4.7 vs. 16.4 ± 3.3% in MI-control; P < 0.05). Furthermore, GScir and GSr appeared to be the best parameters to identify a TEMI >0.75 24 h after reperfusion. In conclusion, these findings demonstrate the usefulness of speckle tracking imaging in the early evaluation of a cardioprotective strategy in a rat model of ischemia-reperfusion.

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Connexin 43 phosphorylation by casein kinase 1 is essential for the cardioprotection by ischemic preconditioning

Basic Research in Cardiology ◽

10.1007/s00395-021-00861-z ◽

2021 ◽

Vol 116 (1) ◽

Author(s):

Christine Hirschhäuser ◽

Alessio Lissoni ◽

Philipp Maximilian Görge ◽

Paul D. Lampe ◽

Jacqueline Heger ◽

...

Keyword(s):

Protein Kinase ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Connexin 43 ◽

Ischemia Reperfusion ◽

Casein Kinase ◽

Mitogen Activated Protein Kinase ◽

Myocardial Infarct Size ◽

Open Probability ◽

Casein Kinase 1

AbstractMyocardial connexin 43 (Cx43) forms gap junctions and hemichannels, and is also present within subsarcolemmal mitochondria. The protein is phosphorylated by several kinases including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and casein kinase 1 (CK1). A reduction in Cx43 content abrogates myocardial infarct size reduction by ischemic preconditioning (IPC). The present study characterizes the contribution of Cx43 phosphorylation towards mitochondrial function, hemichannel activity, and the cardioprotection by IPC in wild-type (WT) mice and in mice in which Cx43-phosphorylation sites targeted by above kinases are mutated to non-phosphorylatable residues (Cx43MAPKmut, Cx43PKCmut, and Cx43CK1mut mice). The amount of Cx43 in the left ventricle and in mitochondria was reduced in all mutant strains compared to WT mice and Cx43 phosphorylation was altered at residues not directly targeted by the mutations. Whereas complex 1 respiration was reduced in all strains, complex 2 respiration was decreased in Cx43CK1mut mice only. In Cx43 epitope-mutated mice, formation of reactive oxygen species and opening of the mitochondrial permeability transition pore were not affected. The hemichannel open probability was reduced in Cx43PKCmut and Cx43CK1mut but not in Cx43MAPKmut cardiomyocytes. Infarct size in isolated saline-perfused hearts after ischemia/reperfusion (45 min/120 min) was comparable between genotypes and was significantly reduced by IPC (3 × 3 min ischemia/5 min reperfusion) in WT, Cx43MAPKmut, and Cx43PKCmut, but not in Cx43CK1mut mice, an effect independent from the amount of Cx43 and the probability of hemichannel opening. Taken together, our study shows that alterations of Cx43 phosphorylation affect specific cellular functions and highlights the importance of Cx43 phosphorylation by CK1 for IPC’s cardioprotection.

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