• 5-hydroxytryptophan
• cardiotoxicity
• chemotherapy
• collagen
• gap junction

• Mice
• Animals
• Myocytes, Cardiac/metabolism
• 5-Hydroxytryptophan/metabolism
• 5-Hydroxytryptophan/pharmacology
• Doxorubicin/toxicity
• Antibiotics, Antineoplastic/pharmacology
• Cardiotoxicity/pathology
• Mitochondrial Diseases/metabolism
• Apoptosis

• Cardiomyocytes
• Cell death
• Ferroptosis
• Myocardial infarction
• Reperfusion injury

• Animals
• Mice
• Humans
• Myocytes, Cardiac
• Cicatrix
• Ferroptosis
• Cell Death
• Heart Injuries
• Reperfusion Injury

• P20 GM113134 NIGMS NIH HHS
• T32 HL115505 NHLBI NIH HHS
• U54 MD007601 NIMHD NIH HHS

• Autophagy
• Cadmium
• Connexin 43
• Hepatocytes
• Rat

• Angiotensin II
• Connexin 43
• Gap junction
• Propofol

• 82072216 National Natural Science Foundation of China
• 2022A1515011556 Guangdong Basic and Applied Basic Research Foundation

• T32 GM007739 NIGMS NIH HHS

• Connexin43
• GJA1-20k
• ischemia
• ischemic precondioning
• mitochondria
• reperfusion

• adiponectin
• apoptosis
• cocaine
• connexin 43
• contraction band necrosis
• mitochondria

• Adiponectin/pharmacology
• Animals
• Cocaine/pharmacology
• Connexin 43/pharmacology
• Myocardium/pathology
• Myocytes, Cardiac
• Necrosis/pathology
• Rats

• Apoptosis
• Dementia
• HIV
• NeuroHIV
• Reservoirs

• Astrocytes/metabolism
• Calcium/metabolism
• HIV Infections/complications
• HIV Infections/metabolism
• Humans
• Inositol Phosphates/metabolism
• Mitochondria

• R01 MH096625 NIMH NIH HHS
• R01 MH128082 NIMH NIH HHS
• R01 NS105584 NINDS NIH HHS

• Cx43
• cardiomyocyte
• connexin
• gap junction
• heart
• hemichannel
• mitochondria
• nucleus

Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in pigs submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty pigs were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC). Plasma was obtained from femoral and great cardiac veins and analyzed by LC-MS/MS. Malonate, RIC, and malonate + RIC reduced infarct size (24.67 ± 5.98, 25.29 ± 3.92 and 29.83 ± 4.62% vs. 46.47 ± 4.49% in controls, p < 0.05), but no additive effects were detected. Enhanced concentrations of succinate, fumarate, malate and citrate were observed in controls during initial reperfusion in the great cardiac vein, and most were reduced by cardioprotective maneuvers. Concentrations of succinate, fumarate, and malate significantly correlated with infarct size. In conclusion, despite the combination of SDH inhibition during reperfusion and RIC did not result in additive protection, plasma concentrations of selected citric acid cycle metabolites are attenuated by protective maneuvers, correlate with irreversible injury, and might become a prognosis tool in STEMI patients.

• ischemia-reperfusion
• malonate
• myocardial infarction
• remote ischemic conditioning
• succinate dehydrogenase

• connexin 43
• diabetes
• endoplasmic reticulum stress
• gap junctions
• insulin resistance
• intercellular communication
• unfolded protein response

Since the mid-20th century, ischemic heart disease has been the world’s leading cause of death. Developing effective clinical cardioprotection strategies would make a significant impact in improving both quality of life and longevity in the worldwide population. Both ex vivo and in vivo animal models of cardiac ischemia/reperfusion (I/R) injury are robustly used in research. Connexin43 (Cx43), the predominant gap junction channel-forming protein in cardiomyocytes, has emerged as a cardioprotective target. Cx43 posttranslational modifications as well as cellular distribution are altered during cardiac reperfusion injury, inducing phosphorylation states and localization detrimental to maintaining intercellular communication and cardiac conduction. Pre- (before ischemia) and post- (after ischemia but before reperfusion) conditioning can abrogate this injury process, preserving Cx43 and reducing cell death. Pre-/post-conditioning has been shown to largely rely on the presence of Cx43, including mitochondrial Cx43, which is implicated to play a major role in pre-conditioning. Posttranslational modifications of Cx43 after injury alter the protein interactome, inducing negative protein cascades and altering protein trafficking, which then causes further damage post-I/R injury. Recently, several peptides based on the Cx43 sequence have been found to successfully diminish cardiac injury in pre-clinical studies.

• Cx43
• cardioprotection
• connexin
• gap junction
• hemi-channel
• ischemia/reperfusion injury
• myocardial infarction

• Animals
• Cardiotonic Agents/metabolism
• Connexin 43/chemistry
• Connexin 43/metabolism
• Disease Models, Animal
• Gap Junctions/metabolism
• Humans
• In Vitro Techniques
• Mitochondria, Heart/metabolism
• Models, Cardiovascular
• Myocardial Ischemia/metabolism
• Myocardial Ischemia/pathology
• Myocardial Ischemia/prevention & control
• Myocardial Reperfusion Injury/metabolism
• Myocardial Reperfusion Injury/pathology
• Myocardial Reperfusion Injury/prevention & control
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology

• EU-CARDIOPROTECTION CA16225 European Cooperation in Science and Technology
• 310030_182573 Swiss National Science Foundation
• IZCOZ0_189878 Swiss National Science Foundation
• 310030E-176050 Swiss National Science Foundation
• G020018N FWO
• POCI-01-0145-FEDER-016385 ERDF
• CENTRO-01-0145-FEDER-000012-N2323; POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, POCI-01-0145-FEDER-022122, FCTUID/NEU/04539/2013, UID/NEU/04539/2019, UIDB/04539/2020 and UIDP/04539/2020 ERDF
• SFRH/BD/115003/2016 FCT
• 858014 European Union's Horizon 2020 Future and Emerging Technologies program

• Connexin 43
• Gap junction
• Hemichannel
• Pulpitis
• Vital pulp therapy

• MPTP
• STEMI
• cardiomyocyte death
• cardioprotection
• ischemia/reperfusion injury
• ischemic conditioning.

• Apoptosis
• Burn
• Cell death
• Connexin

• Adult
• Aged
• Apoptosis
• Burns/metabolism
• Burns/pathology
• Bystander Effect
• Caspase 3/metabolism
• Connexin 43/metabolism
• Dermis/metabolism
• Dermis/pathology
• Disease Progression
• Female
• Fibroblasts/metabolism
• Gap Junctions/metabolism
• HSP47 Heat-Shock Proteins/metabolism
• Humans
• Male
• Middle Aged

Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43^+/- mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed to assess changes in scar size and left ventricular remodeling following transient myocardial ischemia (45 min) followed by 14 days of reperfusion using Cx43^fl/fl (controls) and Cx43^Cre-ER(T)/fl inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele. The scar area (picrosirius red), measured 14 days after transient coronary occlusion, was similarly reduced in both vehicle and 4-OHT-treated Cx43^Cre-ER(T)/fl mice, compared to Cx43^fl/fl animals, having normal Cx43 levels (15.78% ± 3.42% and 16.54% ± 2.31% vs. 25.40% ± 3.14% and 22.43% ± 3.88% in vehicle and 4-OHT-treated mice, respectively, p = 0.027). Left ventricular dilatation was significantly attenuated in both Cx43-deficient groups (p = 0.037 for left ventricular end-diastolic diameter). These protective effects were correlated with an attenuated enhancement in pro-transforming growth factor beta 1 (TGFβ1) expression after reperfusion. In conclusion, our data demonstrate that Cx43 deficiency induces a protective effect on scar formation after transient coronary occlusion in mice, an effect associated with reduced left ventricular remodeling and attenuated enhancement in pro-TGFβ1 expression.

• collagen
• connexin 43
• ischemia–reperfusion
• left ventricular remodeling
• myocardial infarct

• Compound drug
• Myocardial infarction
• Reperfusion injury

Connexin 43 (Cx43) is essential for cardiac electrical coupling, but its effects on myocardial fibrosis is controversial. Here, we analyzed the role of Cx43 in myocardial fibrosis caused by angiotensin II (AngII) using Cx43^fl/fl and Cx43^Cre-ER(T)/fl inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele. Myocardial collagen content was enhanced by AngII in all groups (n = 8–10/group, p < 0.05). However, animals with partial Cx43 deficiency (vehicle-treated Cx43^Cre-ER(T)/fl) had a significantly higher AngII-induced collagen accumulation that reverted when treated with 4-OHT, which abolished Cx43 expression. The exaggerated fibrotic response to AngII in partially deficient Cx43^Cre-ER(T)/fl mice was associated with enhanced p38 MAPK activation and was not evident in Cx43 heterozygous (Cx43^+/-) mice. In contrast, normalization of interstitial collagen in 4-OHT-treated Cx43^Cre-ER(T)/fl animals correlated with enhanced MMP-9 activity, IL-6 and NOX2 mRNA expression, and macrophage content, and with reduced α-SMA and SM22α in isolated fibroblasts. In conclusion, our data demonstrates an exaggerated, p38 MAPK-dependent, fibrotic response to AngII in partially deficient Cx43^Cre-ER(T)/fl mice, and a paradoxical normalization of collagen deposition in animals with an almost complete Cx43 ablation, an effect associated with increased MMP-9 activity and inflammatory response and reduced fibroblasts differentiation.

• angiotensin II
• collagen
• connexin 43
• fibrosis
• hypertrophy

• Cirrhosis
• Connexins
• Gap junctions
• Hemichannels
• Intercellular communication
• Liver

Cell-cell communication via gap junctions regulates a wide range of physiological processes by enabling the direct intercellular electrical and chemical coupling. However, the in vivo distribution and function of gap junctions remain poorly understood, partly due to the lack of non-invasive tools with both cell-type specificity and high spatiotemporal resolution. Here, we developed PARIS (pairing actuators and receivers to optically isolate gap junctions), a new fully genetically encoded tool for measuring the cell-specific gap junctional coupling (GJC). PARIS successfully enabled monitoring of GJC in several cultured cell lines under physiologically relevant conditions and in distinct genetically defined neurons in Drosophila brain, with ~10 s temporal resolution and sub-cellular spatial resolution. These results demonstrate that PARIS is a robust, highly sensitive tool for mapping functional gap junctions and study their regulation in both health and disease.

For the tissues and organs of our bodies to work properly, the cells within them need to communicate with each other. One important part of cellular communication is the movement of signals – usually small molecules or ions – directly from one cell to another. This happens via structures called gap junctions, a type of sealed ‘channel’ that connects two cells.

Gap junctions are found throughout the body, but investigating their precise roles in health and disease has been difficult. This is due to problems with the tools available to detect and monitor gap junctions. Some are simply harmful to cells, while others cannot be restricted to specific cell populations within a tissue. This lack of specificity makes it difficult to study gap junctions in the brain, where it is important to understand the connectivity patterns between distinct types of nerve cells. Wu et al. wanted to develop a new, non-harmful method to track gap junctions in distinct groups of cells within living tissues.

To do this, Wu et al. devised PARIS, a two-part, genetically encoded system. The first part comprises a light-sensitive molecular ‘pump’, which can only be turned on by shining a laser onto the cell of interest. When the pump is active, it transports hydrogen ions out of the cell. The second part of the system is a fluorescent sensor, present inside ‘receiving’ cells, which responds to the outcoming hydrogen ions (small enough to pass through gap junctions). If an illuminated ‘signaling’ cell is connected via gap junctions to cells containing the fluorescent sensor, they will light up within seconds, but other cells not connected through gap junctions will not.

The researchers first tested PARIS in cultured human and rat cells that had been genetically engineered to produce both components of the system. The experiments confirmed that PARIS could both detect networks of gap junctions in healthy cells and reveal when these networks had been disrupted, for instance by drugs or genetic mutations. Experiments using fruit flies demonstrated that PARIS was stable in living tissue and could also map the gap junctions connecting specific groups of nerve cells.

PARIS is a valuable addition to the toolbox available to study cell communication. In the future, it could help increase our understanding of diseases characterized by defective gap junctions, such as seizures, cardiac irregularities, and even some cancers.

• D. melanogaster
• cardiomyocytes
• electrical synapses
• gap junctions
• neuroscience
• olfactory system
• optogenetics

• capacity regulation
• hemichannels
• ischemic preconditioning
• myocardial protection

Oxygen-glucose deprivation-nutrition resumption (OGD-NR) models on H9c2 cells are commonly used in vitro models of simulated myocardial ischemia-reperfusion injury (MIRI), but no study has assessed whether these methods for establishing in vitro models can effectively imitate the characteristics of MIRI in vivo. This experiment was designed to analyze the feasibility of six OGD-NR models of MIRI.

By searching the PubMed database using the keywords “myocardial reperfusion injury H9c2 cells,” we obtained six commonly used OGD-NR in vitro models of MIRI performed on H9c2 cells from more than 400 published papers before January 30, 2017. For each model, control (C), simulated ischemia (SI), and simulated ischemia-reperfusion (SIR) groups were assigned, and cell morphology, lactate dehydrogenase (LDH) release, adenosine triphosphate (ATP) levels, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory cytokines were examined to evaluate the characteristics of cell injury. Subsequently, a coculture system of cardiomyocyte-endothelial-macrophage was constructed. The coculture system was dealt with SI and SIR treatments to test the effect on cardiomyocytes survival.

For models 1, 2, 3, 4, 5, and 6, SI treatment caused morphological damage to cells, and subsequent SIR treatment did not cause further morphological damage. In the models 1, 2, 3, 4, 5 and 6, LDH release was significantly higher in the SI groups than that in the C group (P < 0.05), and was significantly lower in the SIR groups than that in the SI groups (P < 0.05), except for no significant differences in the LDH release between C, SI and SIR groups in model 6 receiving a 3-h SI treatment. In models 1, 2, 3, 4, 5, and 6, compared with the C group, ATP levels of the SI groups significantly decreased (P < 0.05), ROS levels increased (P < 0.05), and MMP levels decreased (P < 0.05). Compared with the SI group, ATP level of the SIR groups was significantly increased (P < 0.05), and there was no significant ROS production, MMP collapse, and over inflammatory response in the SIR groups. In a coculture system of H9c2 cells-endothelial cells-macrophages, the proportion of viable H9c2 cells in the SIR groups was not reduced compared with the SI groups.

All the six OGD-NR models on H9c2 cells in this experiment can not imitate the characteristics of MIRI in vivo and are not suitable for MIRI-related study.

• Feasibility
• In vitro
• Models
• Myocardial Ischemia-Reperfusion Injury

• Animals
• Biomedical Research/methods
• Biomedical Research/standards
• Cardiology/methods
• Cardiology/standards
• Cardiovascular Agents/therapeutic use
• Data Accuracy
• Data Interpretation, Statistical
• Disease Models, Animal
• Drug Evaluation, Preclinical/methods
• Drug Evaluation, Preclinical/standards
• Humans
• Ischemic Preconditioning, Myocardial/methods
• Ischemic Preconditioning, Myocardial/standards
• Myocardial Infarction/metabolism
• Myocardial Infarction/pathology
• Myocardial Infarction/physiopathology
• Myocardial Infarction/prevention & control
• Myocardial Reperfusion Injury/metabolism
• Myocardial Reperfusion Injury/pathology
• Myocardial Reperfusion Injury/physiopathology
• Myocardial Reperfusion Injury/prevention & control
• Reproducibility of Results
• Research Design/standards

• FS/10/039/28270 British Heart Foundation
• PG/18/44/33790 British Heart Foundation
• The Danish Council for Strategic Research
• Novo Nordisk Fonden
• TrygFonden
• National Institute for Health Research University College London Hospitals
• Duke National University Singapore Medical School
• Singapore Ministry of Health’s National Medical Research Council and its Clinician Scientist-Senior Investigator scheme
• Health’s National Medical Research Council and Collaborative Centre Grant scheme
• Hungarian National Research, Development, and Innovation Office
• Ministry of Human Capacities
• Bolyai Scholarship by the Hungarian Academy of Sciences
• Deutsche Forschungsgemeinschaft

• Arrhythmia
• Cardiac excitation wave
• Ethanol
• Heptanol
• Optical mapping
• Uncoupling

Inhibition of succinate dehydrogenase (SDH) with malonate during reperfusion reduces infarct size in isolated mice hearts submitted to global ischemia. However, malonate has toxic effects that preclude its systemic administration in animals. Here we investigated the effect of intracoronary malonate on infarct size in pigs submitted to transient coronary occlusion. Under baseline conditions, 50 mmol/L of intracoronary disodium malonate, but not lower concentrations, transiently reduced systolic segment shortening in the region perfused by the left anterior descending coronary artery (LAD) in open-chest pigs. To assess the effects of SDH inhibition on reperfusion injury, saline or malonate 10 mmol/L were selectively infused into the area at risk in 38 animals submitted to ischemia-reperfusion. Malonate improved systolic shortening in the area at risk two hours after 15 min of ischemia (0.18 ± 0.07 vs 0.00 ± 0.01 a.u., p = 0.025, n = 3). In animals submitted to 40 min of ischemia, malonate reduced reactive oxygen species production (MitoSOX staining) during initial reperfusion and limited infarct size (36.46 ± 5.35 vs 59.62 ± 4.00%, p = 0.002, n = 11), without modifying reperfusion arrhythmias. In conclusion, inhibition of SDH with intracoronary malonate during early reperfusion limits reperfusion injury and infarct size in pigs submitted to transient coronary occlusion without modifying reperfusion arrhythmias or contractile function in distant myocardium.

• Cx43
• Cytoprotection
• KATP channel
• Kir6.1

Cardiac connexin43 (Cx43) serves an essential role in maintaining the functional integrity of the heart. The present study investigated the effect of glucose deprivation (GD) on Cx43 protein expression levels in H9c2 cells, and demonstrated that following 2 h GD, Cx43 protein expression levels in H9c2 cells increased by ~68%. In addition, GD activated the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway, which regulated the expression levels of cardiac Cx43. A MAPK inhibitor and U0126, an ERK inhibitor, abolished the effects of GD on Cx43 expression levels. Under GD, the protein expression levels of Beclin-1, p62 and LC3 were augmented, and were decreased in the presence of ERK inhibitor or siRNA-ERK. In addition, H9c2 cells exposed to GD exhibited marked increase in LDH release and decreased MTT reduction activity, all of which were not significantly reversed by U0126 treatment. Therefore, the ERK/MAPK signaling pathway may be involved in elevating cardiac Cx43 expression levels under GD in H9c2 cells.

• Connexin 43
• Extracellular vesicles
• GJA1
• Gap junction
• Intercellular communication
• Tunnelling nanotube

• Clinical implication
• Ischaemic preconditioning
• Mechanism

• Animals
• Humans
• Ischemic Preconditioning/methods
• Myocardial Infarction/therapy

• Gap junctions
• Hemichannels
• Mitochondrial metabolism
• Mitochondrial respiration
• Radical oxygen species
• Reperfusion injury

• Atrial fibrillation
• Gap junction
• PQ1
• Pacemaker current
• Pulmonary vein
• Sinoatrial node

• gap junction uncoupling
• ischemia
• neonates

• Apoptosis
• Caspases
• Ischemia
• Myocardium
• Reperfusion

Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) applied by brief ischemic episodes to heart-distant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of rIPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling - receptor-dependent and independently. Cellular targets include deleterious calcium (Ca²⁺) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC. This refers to the protective role of nitrite, which can be activated endogenously using rIPC and which then contributes to cardioprotection by rIPC.

• Remote ischemic preconditioning
• Ischemia/reperfusion injury
• Nitrite
• S-nitrosation
• Mitochondria

Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia‐reperfusion injury (IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof‐of‐concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered – the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.

This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8

• Gap junction
• Heart
• Morphogenesis
• Remodeling

• Blood Pressure/physiology
• Connexins/genetics
• Connexins/metabolism
• Electromagnetic Fields
• Epigenesis, Genetic/physiology
• Gap Junctions/physiology
• Heart/embryology
• Humans
• Models, Cardiovascular
• Morphogenesis/physiology
• Myocardial Contraction/physiology
• Ventricular Remodeling/physiology

Remote ischemic preconditioning (RIPC) protects the heart from ischemia and reperfusion (I/R) injury. The underlying molecular mechanisms are unclear. It has been demonstrated that Connexin 43 (Cx43) is critically involved in cardioprotective interventions including classical ischemic preconditioning. In the present study we investigated the influence of RIPC on the expression patterns of Cx43 after I/R in the rat heart in vivo.

Male Wistar rats were subjected to 35 min regional myocardial ischemia followed by 2 h reperfusion with or without 4 cycles of 5 minutes bilateral hind limb ischemia and reperfusion (RIPC), to RIPC without ischemia or underwent no intervention (Sham). Infarct size was measured by TTC staining. The myocardium was divided into area at risk (AAR) and area not at risk (non AAR). Expression of Cx43-mRNA and protein was analyzed by qPCR and Western Blot analysis, respectively. Localization of Cx43 was visualized by confocal immunofluorescence staining.

RIPC reduced the infarct size (I/R: 73 ± 5% vs. RIPC I/R: 34 ± 14%, p < 0.05). Expression of Cx43 mRNA did not differ between groups. I/R caused a strong decrease of relative Cx43 protein expression in the AAR that was partly abolished by RIPC. Furthermore, RIPC decreased the level of ischemia-induced dephosphorylation of Cx43. Confocal immunofluorescence staining showed that I/R caused a loss of the Cx43 signal at the intercalated discs, while the Cx43 signal at the intercalated discs was partly sustained after RIPC.

Preservation of Cx43 protein expression and phosphorylation after RIPC might protect the rat heart in vivo.

The online version of this article (doi:10.1186/s12967-014-0228-8) contains supplementary material, which is available to authorized users.

• 3D Imaging
• LV remodeling
• animals
• ischemia–reperfusion
• myofiber

• Cardiac ischaemia/reperfusion injury
• Cx40
• Gap junction
• Neutrophil recruitment

• 5'-Nucleotidase/metabolism
• Animals
• Connexin 43/metabolism
• Connexins/metabolism
• Disease Models, Animal
• Endothelial Cells/metabolism
• Endothelium, Vascular/metabolism
• Gap Junctions/metabolism
• Ischemia/metabolism
• Mice
• Myocardial Reperfusion Injury/metabolism
• Neutrophil Infiltration/physiology
• Gap Junction alpha-5 Protein

• Animals
• Blood Vessels/cytology
• Blood Vessels/metabolism
• Cell Communication/physiology
• Cell Membrane/metabolism
• Endothelium, Vascular/cytology
• Endothelium, Vascular/metabolism
• Gap Junctions/metabolism
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Ion Channels/metabolism
• Membrane Microdomains/metabolism
• Paracrine Communication/physiology

• R21 HL107963 NHLBI NIH HHS
• HL088554 NHLBI NIH HHS
• HL107963 NHLBI NIH HHS
• R01 HL088554 NHLBI NIH HHS
• T32 HL007284 NHLBI NIH HHS

• arrhythmias
• gap junction
• ischemia/reperfusion
• nitric oxide