Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection
<p>Mouse heart on a Langendorff perfusion system. (<b>A</b>) Schematic representation and (<b>B</b>) photograph of the cannulated heart. The isolated heart is cannulated via the aorta in order to be perfused with oxygenated, nutrient-rich Krebs solution. A balloon, connected to a pressure transducer, is inserted in the left ventricle for myocardial function measurements. To maintain 37 °C, the heart is immersed in a thermal chamber containing Krebs solution during the entire ex vivo procedure.</p> "> Figure 2
<p>Schematic representation of the left anterior descending (LAD) ligation to induce in vivo ischemia/reperfusion (I/R) injury in mice. (<b>A</b>) After the induction of anesthesia, the mouse is placed in supine position and intubated. The chest is opened by performing a lateral incision of the left sternum side. (<b>B</b>,<b>C</b>) Separating the third and the fourth rib exposes the heart, allowing a prolene suture to be placed around the LAD in a snare that is then closed in order to induce ischemia. Reperfusion is performed 30 min later by releasing the snare. (<b>D</b>) In order to determine the area at risk (AAR), the LAD is re-occluded after reperfusion and Evans blue is injected intravenously. The dye stains all perfused tissues, including the right ventricle (RV) and part of the left ventricle (LV). The heart is sectioned into thin 1 mm slices and incubated with triphenyltetrazolium chloride (TTC) to determine the AAR (outlined in red) and the infarcted area (IA; outlined in white). Scale bar represents 50 μm.</p> "> Figure 3
<p>Structure of connexin (Cx) channels. (<b>A</b>) Cx topology is highly conserved, being composed of 9 structural domains, i.e., intracellular N-terminus (NT), cytoplasmic loop (CL) and C-terminus (CT), two extracellular loops (EL1 and EL2) and 4 α-helical transmembrane domains (TM1–TM4). (<b>B</b>) Gap junction channels are formed by the docking of 2 hemi-channels (or connexons) in apposed plasma membranes of adjacent cells. Each connexon is composed by the assembly of 6 connexin proteins. Gap junction channels allow the direct transfer of small molecules or ions between the cytoplasms of neighboring cells, whereas hemi-channels mediate the communication with the extracellular milieu.</p> "> Figure 4
<p>Cx43 immunofluorescent staining (in red) in Langendorff-perfused hearts subjected to ex vivo I/R. (<b>A</b>) End of stabilization period. (<b>B</b>) After 30 min of global no-flow ischemia. (<b>C</b>) After 30 min of global no-flow ischemia and 5 min reperfusion. (<b>D</b>) After 30 min of global no-flow ischemia and 60 min reperfusion. Nuclei are stained with 4′,6′-diamidino-2-phenylindole (DAPI) (in blue). Scale bar represents 20 μm.</p> "> Figure 5
<p>The cardiac Cx43 interactome alters in I/R-induced gap junction remodeling. A schematic representation of the subcellular localization of some relevant Cx43 interacting proteins in healthy (left; in pink) and injured (right; in brown) cardiomyocytes.</p> ">
Abstract
:1. Introduction
2. Pathophysiology of Cardiac I/R Injury
3. Methods Used to Study Cardiac I/R Injury
3.1. Ex Vivo Perfused Heart as a Model for I/R Injury
3.2. In Vivo Models of Cardiac I/R Injury
4. Canonical Role of Connexin43 in I/R Injury and Cardioprotection
4.1. Cx43 Gap Junction- and Hemi-Channels and Cardiac I/R Injury
4.2. Potential Role of Cx43 in Non-Cardiac Cells of the Heart in I/R Injury
5. Non-Canonical Role of Connexin43 in I/R Injury and Cardioprotection
5.1. Mitochondrial Cx43 and Cardiac I/R Injury
5.2. Cx43 Protein Partners and Their Role in Cardiac I/R Injury-Mediated Gap Junction Remodeling
6. Concluding Remarks: On the Way Towards Cx43-Targeted Strategies for Cardioprotection
Funding
Conflicts of Interest
References
- Joseph, P.; Leong, D.; McKee, M.; Anand, S.S.; Schwalm, J.D.; Teo, K.; Mente, A.; Yusuf, S. Reducing the global burden of cardiovascular disease, part 1: The epidemiology and risk factors. Circ. Res. 2017, 121, 677–694. [Google Scholar] [CrossRef] [PubMed]
- Libby, P.; Pasterkamp, G.; Crea, F.; Jang, I.K. Reassessing the mechanisms of acute coronary syndromes. Circ. Res. 2019, 124, 150–160. [Google Scholar] [CrossRef] [PubMed]
- Davidson, S.M.; Ferdinandy, P.; Andreadou, I.; Botker, H.E.; Heusch, G.; Ibanez, B.; Ovize, M.; Schulz, R.; Yellon, D.M.; Hausenloy, D.J.; et al. Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J. Am. Coll. Cardiol. 2019, 73, 89–99. [Google Scholar] [CrossRef] [PubMed]
- Rossello, X.; Yellon, D.M. Cardioprotection: The disconnect between bench and bedside. Circulation 2016, 134, 574–575. [Google Scholar] [CrossRef] [PubMed]
- Heusch, G. Cardioprotection research must leave its comfort zone. Eur. Heart J. 2018, 39, 3393–3395. [Google Scholar] [CrossRef] [Green Version]
- Yellon, D.M.; Hausenloy, D.J. Myocardial reperfusion injury. N. Engl. J. Med. 2007, 357, 1121–1135. [Google Scholar] [CrossRef]
- Heusch, G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat. Rev. Cardiol. 2020. [Google Scholar] [CrossRef]
- Hausenloy, D.J.; Yellon, D.M. Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J. Clin. Investig. 2013, 123, 92–100. [Google Scholar] [CrossRef]
- Hausenloy, D.J.; Schulz, R.; Girao, H.; Kwak, B.R.; De Stefani, D.; Rizzuto, R.; Bernardi, P.; Di Lisa, F. Mitochondrial ion channels as targets for cardioprotection. J. Cell. Mol. Med. 2020. [Google Scholar] [CrossRef]
- Montecucco, F.; Carbone, F.; Schindler, T.H. Pathophysiology of ST-segment elevation myocardial infarction: Novel mechanisms and treatments. Eur. Heart J. 2016, 37, 1268–1283. [Google Scholar] [CrossRef] [Green Version]
- Frank, A.; Bonney, M.; Bonney, S.; Weitzel, L.; Koeppen, M.; Eckle, T. Myocardial ischemia reperfusion injury: From basic science to clinical bedside. Semin. Cardiothorac. Vasc. Anesth. 2012, 16, 123–132. [Google Scholar] [CrossRef] [PubMed]
- Kumar, M.; Kasala, E.R.; Bodduluru, L.N.; Dahiya, V.; Sharma, D.; Kumar, V.; Lahkar, M. Animal models of myocardial infarction: Mainstay in clinical translation. Regul. Toxicol. Pharmacol. 2016, 76, 221–230. [Google Scholar] [CrossRef] [PubMed]
- Ludman, A.J.; Yellon, D.M.; Hausenloy, D.J. Cardiac preconditioning for ischaemia: Lost in translation. Dis. Models Mech. 2010, 3, 35–38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McCafferty, K.; Forbes, S.; Thiemermann, C.; Yaqoob, M.M. The challenge of translating ischemic conditioning from animal models to humans: The role of comorbidities. Dis. Models Mech. 2014, 7, 1321–1333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lindsey, M.L.; Bolli, R.; Canty, J.M., Jr.; Du, X.J.; Frangogiannis, N.G.; Frantz, S.; Gourdie, R.G.; Holmes, J.W.; Jones, S.P.; Kloner, R.A.; et al. Guidelines for experimental models of myocardial ischemia and infarction. Am. J. Physiol. Heart Circ. Physiol. 2018, 314, H812–H838. [Google Scholar] [CrossRef] [PubMed]
- Liao, R.; Podesser, B.K.; Lim, C.C. The continuing evolution of the Langendorff and ejecting murine heart: New advances in cardiac phenotyping. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H156–H167. [Google Scholar] [CrossRef]
- Sutherland, F.J.; Hearse, D.J. The isolated blood and perfusion fluid perfused heart. Pharmacol. Res. 2000, 41, 613–627. [Google Scholar] [CrossRef]
- Langendorff, O. Untersuchungen am überlebenden Säugethierherzen. Arch. Gesamte Physiol. Menschen Tiere 1895, 61, 291–332. [Google Scholar] [CrossRef]
- Sutherland, F.J.; Shattock, M.J.; Baker, K.E.; Hearse, D.J. Mouse isolated perfused heart: Characteristics and cautions. Clin. Exp. Pharmacol. Physiol. 2003, 30, 867–878. [Google Scholar] [CrossRef]
- Bell, R.M.; Mocanu, M.M.; Yellon, D.M. Retrograde heart perfusion: The Langendorff technique of isolated heart perfusion. J. Mol. Cell. Cardiol. 2011, 50, 940–950. [Google Scholar] [CrossRef]
- Curtis, M.J.; Hancox, J.C.; Farkas, A.; Wainwright, C.L.; Stables, C.L.; Saint, D.A.; Clements-Jewery, H.; Lambiase, P.D.; Billman, G.E.; Janse, M.J.; et al. The Lambeth Conventions (II): Guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol. Ther. 2013, 139, 213–248. [Google Scholar] [CrossRef] [PubMed]
- Mersmann, J.; Latsch, K.; Habeck, K.; Zacharowski, K. Measure for measure-determination of infarct size in murine models of myocardial ischemia and reperfusion: A systematic review. Shock 2011, 35, 449–455. [Google Scholar] [CrossRef] [PubMed]
- Ferrera, R.; Benhabbouche, S.; Bopassa, J.C.; Li, B.; Ovize, M. One hour reperfusion is enough to assess function and infarct size with TTC staining in Langendorff rat model. Cardiovasc. Drugs Ther. 2009, 23, 327–331. [Google Scholar] [CrossRef] [PubMed]
- Headrick, J.P.; Peart, J.; Hack, B.; Flood, A.; Matherne, G.P. Functional properties and responses to ischaemia-reperfusion in Langendorff perfused mouse heart. Exp. Physiol. 2001, 86, 703–716. [Google Scholar] [CrossRef]
- Fishbein, M.C.; Meerbaum, S.; Rit, J.; Lando, U.; Kanmatsuse, K.; Mercier, J.C.; Corday, E.; Ganz, W. Early phase acute myocardial infarct size quantification: Validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am. Heart J. 1981, 101, 593–600. [Google Scholar] [CrossRef]
- Redfors, B.; Shao, Y.; Omerovic, E. Myocardial infarct size and area at risk assessment in mice. Exp. Clin. Cardiol. 2012, 17, 268–272. [Google Scholar]
- Pitoulis, F.G.; Watson, S.A.; Perbellini, F.; Terracciano, C.M. Myocardial slices come to age: An intermediate complexity in vitro cardiac model for translational research. Cardiovasc. Res. 2020, 116, 1275–1287. [Google Scholar] [CrossRef] [Green Version]
- Kolk, M.V.; Meyberg, D.; Deuse, T.; Tang-Quan, K.R.; Robbins, R.C.; Reichenspurner, H.; Schrepfer, S. LAD-ligation: A murine model of myocardial infarction. J. Vis. Exp. 2009. [Google Scholar] [CrossRef]
- Michael, L.H.; Entman, M.L.; Hartley, C.J.; Youker, K.A.; Zhu, J.; Hall, S.R.; Hawkins, H.K.; Berens, K.; Ballantyne, C.M. Myocardial ischemia and reperfusion: A murine model. Am. J. Physiol. 1995, 269, H2147–H2154. [Google Scholar] [CrossRef]
- Verdouw, P.D.; van den Doel, M.A.; de Zeeuw, S.; Duncker, D.J. Animal models in the study of myocardial ischaemia and ischaemic syndromes. Cardiovasc. Res. 1998, 39, 121–135. [Google Scholar] [CrossRef]
- Xu, Z.; McElhanon, K.E.; Beck, E.X.; Weisleder, N. A murine model of myocardial ischemia-reperfusion injury. Methods Mol. Biol. 2018, 1717, 145–153. [Google Scholar] [CrossRef] [PubMed]
- Johns, T.N.; Olson, B.J. Experimental myocardial infarction. I. A method of coronary occlusion in small animals. Ann. Surg. 1954, 140, 675–682. [Google Scholar] [CrossRef] [PubMed]
- Tarnavski, O.; McMullen, J.R.; Schinke, M.; Nie, Q.; Kong, S.; Izumo, S. Mouse cardiac surgery: Comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. Physiol. Genom. 2004, 16, 349–360. [Google Scholar] [CrossRef] [PubMed]
- Gao, E.; Lei, Y.H.; Shang, X.; Huang, Z.M.; Zuo, L.; Boucher, M.; Fan, Q.; Chuprun, J.K.; Ma, X.L.; Koch, W.J. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ. Res. 2010, 107, 1445–1453. [Google Scholar] [CrossRef] [PubMed]
- Morel, S.; Braunersreuther, V.; Chanson, M.; Bouis, D.; Rochemont, V.; Foglia, B.; Pelli, G.; Sutter, E.; Pinsky, D.J.; Mach, F.; et al. Endothelial Cx40 limits myocardial ischaemia/reperfusion injury in mice. Cardiovasc. Res. 2014, 102, 329–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, Z.; Alloush, J.; Beck, E.; Weisleder, N. A murine model of myocardial ischemia-reperfusion injury through ligation of the left anterior descending artery. J. Vis. Exp. 2014. [Google Scholar] [CrossRef]
- Hartley, C.J.; Michael, L.H.; Entman, M.L. Noninvasive measurement of ascending aortic blood velocity in mice. Am. J. Physiol. 1995, 268, H499–H505. [Google Scholar] [CrossRef]
- Morel, S.; Christoffersen, C.; Axelsen, L.N.; Montecucco, F.; Rochemont, V.; Frias, M.A.; Mach, F.; James, R.W.; Naus, C.C.; Chanson, M.; et al. Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. Cardiovasc. Res. 2016, 109, 385–396. [Google Scholar] [CrossRef] [Green Version]
- Stopa, B.; Rybarska, J.; Drozd, A.; Konieczny, L.; Krol, M.; Lisowski, M.; Piekarska, B.; Roterman, I.; Spolnik, P.; Zemanek, G. Albumin binds self-assembling dyes as specific polymolecular ligands. Int. J. Biol. Macromol. 2006, 40, 1–8. [Google Scholar] [CrossRef]
- Leybaert, L.; Lampe, P.D.; Dhein, S.; Kwak, B.R.; Ferdinandy, P.; Beyer, E.C.; Laird, D.W.; Naus, C.C.; Green, C.R.; Schulz, R. Connexins in cardiovascular and neurovascular health and disease: Pharmacological implications. Pharmacol. Rev. 2017, 69, 396–478. [Google Scholar] [CrossRef]
- Hoagland, D.T.; Santos, W.; Poelzing, S.; Gourdie, R.G. The role of the gap junction perinexus in cardiac conduction: Potential as a novel anti-arrhythmic drug target. Prog. Biophys. Mol. Biol. 2019, 144, 41–50. [Google Scholar] [CrossRef] [PubMed]
- Veeraraghavan, R.; Gourdie, R.G.; Poelzing, S. Mechanisms of cardiac conduction: A history of revisions. Am. J. Physiol. Heart Circ. Physiol. 2014, 306, H619–H627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Veeraraghavan, R.; Hoeker, G.S.; Alvarez-Laviada, A.; Hoagland, D.; Wan, X.; King, D.R.; Sanchez-Alonso, J.; Chen, C.; Jourdan, J.; Isom, L.L.; et al. The adhesion function of the sodium channel beta subunit (beta1) contributes to cardiac action potential propagation. eLife 2018, 7. [Google Scholar] [CrossRef]
- Aasen, T.; Mesnil, M.; Naus, C.C.; Lampe, P.D.; Laird, D.W. Gap junctions and cancer: Communicating for 50 years. Nat. Rev. Cancer 2016, 16, 775–788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laird, D.W.; Lampe, P.D. Therapeutic strategies targeting connexins. Nat. Rev. Drug Discov. 2018, 17, 905–921. [Google Scholar] [CrossRef] [PubMed]
- Martins-Marques, T.; Ribeiro-Rodrigues, T.; Batista-Almeida, D.; Aasen, T.; Kwak, B.R.; Girao, H. Biological functions of Connexin43 beyond intercellular communication. Trends Cell Biol. 2019, 29, 835–847. [Google Scholar] [CrossRef] [PubMed]
- Van Campenhout, R.; Cooreman, A.; Leroy, K.; Rusiecka, O.M.; Van Brantegem, P.; Annaert, P.; Muyldermans, S.; Devoogdt, N.; Cogliati, B.; Kwak, B.R.; et al. Non-canonical roles of connexins. Prog. Biophys. Mol. Biol. 2020, 153, 35–41. [Google Scholar] [CrossRef]
- Severs, N.J.; Bruce, A.F.; Dupont, E.; Rothery, S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc. Res. 2008, 80, 9–19. [Google Scholar] [CrossRef] [Green Version]
- Garcia-Dorado, D.; Rodriguez-Sinovas, A.; Ruiz-Meana, M. Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc. Res. 2004, 61, 386–401. [Google Scholar] [CrossRef]
- Schulz, R.; Gorge, P.M.; Gorbe, A.; Ferdinandy, P.; Lampe, P.D.; Leybaert, L. Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol. Ther. 2015, 153, 90–106. [Google Scholar] [CrossRef] [Green Version]
- Schulz, R.; Gres, P.; Skyschally, A.; Duschin, A.; Belosjorow, S.; Konietzka, I.; Heusch, G. Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J. 2003, 17, 1355–1357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Axelsen, L.N.; Stahlhut, M.; Mohammed, S.; Larsen, B.D.; Nielsen, M.S.; Holstein-Rathlou, N.H.; Andersen, S.; Jensen, O.N.; Hennan, J.K.; Kjolbye, A.L. Identification of ischemia-regulated phosphorylation sites in connexin43: A possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J. Mol. Cell. Cardiol. 2006, 40, 790–798. [Google Scholar] [CrossRef] [PubMed]
- Hawat, G.; Benderdour, M.; Rousseau, G.; Baroudi, G. Connexin 43 mimetic peptide Gap26 confers protection to intact heart against myocardial ischemia injury. Pflug. Arch. 2010, 460, 583–592. [Google Scholar] [CrossRef] [PubMed]
- Morel, S.; Frias, M.A.; Rosker, C.; James, R.W.; Rohr, S.; Kwak, B.R. The natural cardioprotective particle HDL modulates connexin43 gap junction channels. Cardiovasc. Res. 2012, 93, 41–49. [Google Scholar] [CrossRef] [Green Version]
- Surinkaew, S.; Kumphune, S.; Chattipakorn, S.; Chattipakorn, N. Inhibition of p38 MAPK during ischemia, but not reperfusion, effectively attenuates fatal arrhythmia in ischemia/reperfusion heart. J. Cardiovasc. Pharmacol. 2013, 61, 133–141. [Google Scholar] [CrossRef]
- Zhang, P.; Xu, J.; Hu, W.; Yu, D.; Bai, X. Effects of pinocembrin pretreatment on connexin 43 (Cx43) protein expression after rat myocardial ischemia-reperfusion and cardiac arrhythmia. Med. Sci. Monit. 2018, 24, 5008–5014. [Google Scholar] [CrossRef]
- Beardslee, M.A.; Lerner, D.L.; Tadros, P.N.; Laing, J.G.; Beyer, E.C.; Yamada, K.A.; Kleber, A.G.; Schuessler, R.B.; Saffitz, J.E. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ. Res. 2000, 87, 656–662. [Google Scholar] [CrossRef] [Green Version]
- Matsuda, T.; Fujio, Y.; Nariai, T.; Ito, T.; Yamane, M.; Takatani, T.; Takahashi, K.; Azuma, J. N-cadherin signals through Rac1 determine the localization of connexin 43 in cardiac myocytes. J. Mol. Cell. Cardiol. 2006, 40, 495–502. [Google Scholar] [CrossRef]
- Tansey, E.E.; Kwaku, K.F.; Hammer, P.E.; Cowan, D.B.; Federman, M.; Levitsky, S.; McCully, J.D. Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion. Ann. Thorac. Surg. 2006, 82, 1472–1479. [Google Scholar] [CrossRef] [Green Version]
- Bodendiek, S.B.; Raman, G. Connexin modulators and their potential targets under the magnifying glass. Curr. Med. Chem. 2010, 17, 4191–4230. [Google Scholar] [CrossRef]
- Rodriguez-Sinovas, A.; Sanchez, J.A.; Gonzalez-Loyola, A.; Barba, I.; Morente, M.; Aguilar, R.; Agullo, E.; Miro-Casas, E.; Esquerda, N.; Ruiz-Meana, M.; et al. Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischaemia and preconditioning protection. J. Physiol. 2010, 588, 1139–1151. [Google Scholar] [CrossRef] [PubMed]
- Lampe, P.D.; Cooper, C.D.; King, T.J.; Burt, J.M. Analysis of Connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart. J. Cell Sci. 2006, 119, 3435–3442. [Google Scholar] [CrossRef] [Green Version]
- Turner, M.S.; Haywood, G.A.; Andreka, P.; You, L.; Martin, P.E.; Evans, W.H.; Webster, K.A.; Bishopric, N.H. Reversible connexin 43 dephosphorylation during hypoxia and reoxygenation is linked to cellular ATP levels. Circ. Res. 2004, 95, 726–733. [Google Scholar] [CrossRef] [PubMed]
- Lampe, P.D.; TenBroek, E.M.; Burt, J.M.; Kurata, W.E.; Johnson, R.G.; Lau, A.F. Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J. Cell Biol. 2000, 149, 1503–1512. [Google Scholar] [CrossRef] [PubMed]
- Perrelli, M.G.; Pagliaro, P.; Penna, C. Ischemia/reperfusion injury and cardioprotective mechanisms: Role of mitochondria and reactive oxygen species. World J. Cardiol. 2011, 3, 186–200. [Google Scholar] [CrossRef] [PubMed]
- Wang, N.; De Vuyst, E.; Ponsaerts, R.; Boengler, K.; Palacios-Prado, N.; Wauman, J.; Lai, C.P.; De Bock, M.; Decrock, E.; Bol, M.; et al. Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res. Cardiol. 2013, 108, 309. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garcia-Dorado, D.; Inserte, J.; Ruiz-Meana, M.; Gonzalez, M.A.; Solares, J.; Julia, M.; Barrabes, J.A.; Soler-Soler, J. Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion. Circulation 1997, 96, 3579–3586. [Google Scholar] [CrossRef]
- Srisakuldee, W.; Jeyaraman, M.M.; Nickel, B.E.; Tanguy, S.; Jiang, Z.S.; Kardami, E. Phosphorylation of connexin-43 at serine 262 promotes a cardiac injury-resistant state. Cardiovasc. Res. 2009, 83, 672–681. [Google Scholar] [CrossRef] [Green Version]
- Srisakuldee, W.; Makazan, Z.; Nickel, B.E.; Zhang, F.; Thliveris, J.A.; Pasumarthi, K.B.; Kardami, E. The FGF-2-triggered protection of cardiac subsarcolemmal mitochondria from calcium overload is mitochondrial connexin 43-dependent. Cardiovasc. Res. 2014, 103, 72–80. [Google Scholar] [CrossRef] [Green Version]
- Jiang, J.; Hoagland, D.; Palatinus, J.A.; He, H.; Iyyathurai, J.; Jourdan, L.J.; Bultynck, G.; Wang, Z.; Zhang, Z.; Schey, K.; et al. Interaction of alpha carboxyl terminus 1 peptide with the connexin 43 carboxyl terminus preserves left ventricular function after ischemia-reperfusion injury. J. Am. Heart Assoc. 2019, 8, e012385. [Google Scholar] [CrossRef]
- Murry, C.E.; Jennings, R.B.; Reimer, K.A. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986, 74, 1124–1136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shiki, K.; Hearse, D.J. Preconditioning of ischemic myocardium: Reperfusion-induced arrhythmias. Am. J. Physiol. 1987, 253, H1470–H1476. [Google Scholar] [CrossRef] [PubMed]
- Yellon, D.M.; Alkhulaifi, A.M.; Pugsley, W.B. Preconditioning the human myocardium. Lancet 1993, 342, 276–277. [Google Scholar] [CrossRef]
- Zhao, Z.Q.; Corvera, J.S.; Halkos, M.E.; Kerendi, F.; Wang, N.P.; Guyton, R.A.; Vinten-Johansen, J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: Comparison with ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 2003, 285, H579–H588. [Google Scholar] [CrossRef] [PubMed]
- Schwanke, U.; Konietzka, I.; Duschin, A.; Li, X.; Schulz, R.; Heusch, G. No ischemic preconditioning in heterozygous connexin43-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 2002, 283, H1740–H1742. [Google Scholar] [CrossRef]
- Sanchez, J.A.; Rodriguez-Sinovas, A.; Barba, I.; Miro-Casas, E.; Fernandez-Sanz, C.; Ruiz-Meana, M.; Alburquerque-Bejar, J.J.; Garcia-Dorado, D. Activation of RISK and SAFE pathways is not involved in the effects of Cx43 deficiency on tolerance to ischemia-reperfusion injury and preconditioning protection. Basic Res. Cardiol. 2013, 108, 351. [Google Scholar] [CrossRef]
- Li, G.; Whittaker, P.; Yao, M.; Kloner, R.A.; Przyklenk, K. The gap junction uncoupler heptanol abrogates infarct size reduction with preconditioning in mouse hearts. Cardiovasc. Pathol. 2002, 11, 158–165. [Google Scholar] [CrossRef]
- Hatanaka, K.; Kawata, H.; Toyofuku, T.; Yoshida, K. Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in vivo. Jpn. Heart J. 2004, 45, 1007–1019. [Google Scholar] [CrossRef] [Green Version]
- Jain, S.K.; Schuessler, R.B.; Saffitz, J.E. Mechanisms of delayed electrical uncoupling induced by ischemic preconditioning. Circ. Res. 2003, 92, 1138–1144. [Google Scholar] [CrossRef] [Green Version]
- Totzeck, A.; Boengler, K.; van de Sand, A.; Konietzka, I.; Gres, P.; Garcia-Dorado, D.; Heusch, G.; Schulz, R. No impact of protein phosphatases on connexin 43 phosphorylation in ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 2008, 295, H2106–H2112. [Google Scholar] [CrossRef] [Green Version]
- Hund, T.J.; Lerner, D.L.; Yamada, K.A.; Schuessler, R.B.; Saffitz, J.E. Protein kinase Cepsilon mediates salutary effects on electrical coupling induced by ischemic preconditioning. Heart Rhythm 2007, 4, 1183–1193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ando, M.; Katare, R.G.; Kakinuma, Y.; Zhang, D.; Yamasaki, F.; Muramoto, K.; Sato, T. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation 2005, 112, 164–170. [Google Scholar] [CrossRef] [PubMed]
- Heinzel, F.R.; Luo, Y.; Li, X.; Boengler, K.; Buechert, A.; Garcia-Dorado, D.; Di Lisa, F.; Schulz, R.; Heusch, G. Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ. Res. 2005, 97, 583–586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heusch, G.; Buchert, A.; Feldhaus, S.; Schulz, R. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic Res. Cardiol. 2006, 101, 354–356. [Google Scholar] [CrossRef] [PubMed]
- Shinlapawittayatorn, K.; Chinda, K.; Palee, S.; Surinkaew, S.; Kumfu, S.; Kumphune, S.; Chattipakorn, S.; KenKnight, B.H.; Chattipakorn, N. Vagus nerve stimulation initiated late during ischemia, but not reperfusion, exerts cardioprotection via amelioration of cardiac mitochondrial dysfunction. Heart Rhythm 2014, 11, 2278–2287. [Google Scholar] [CrossRef]
- Yue, P.; Zhang, Y.; Du, Z.; Xiao, J.; Pan, Z.; Wang, N.; Yu, H.; Ma, W.; Qin, H.; Wang, W.H.; et al. Ischemia impairs the association between connexin 43 and M3 subtype of acetylcholine muscarinic receptor (M3-mAChR) in ventricular myocytes. Cell. Physiol. Biochem. 2006, 17, 129–136. [Google Scholar] [CrossRef]
- Hausenloy, D.J.; Garcia-Dorado, D.; Botker, H.E.; Davidson, S.M.; Downey, J.; Engel, F.B.; Jennings, R.; Lecour, S.; Leor, J.; Madonna, R.; et al. Novel targets and future strategies for acute cardioprotection: Position paper of the European society of cardiology working group on cellular biology of the heart. Cardiovasc. Res. 2017, 113, 564–585. [Google Scholar] [CrossRef] [Green Version]
- Kolaczkowska, E.; Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 2013, 13, 159–175. [Google Scholar] [CrossRef]
- Eltzschig, H.K.; Eckle, T.; Mager, A.; Kuper, N.; Karcher, C.; Weissmuller, T.; Boengler, K.; Schulz, R.; Robson, S.C.; Colgan, S.P. ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ. Res. 2006, 99, 1100–1108. [Google Scholar] [CrossRef] [Green Version]
- Calder, B.W.; Matthew Rhett, J.; Bainbridge, H.; Fann, S.A.; Gourdie, R.G.; Yost, M.J. Inhibition of connexin 43 hemichannel-mediated ATP release attenuates early inflammation during the foreign body response. Tissue Eng. Part A 2015, 21, 1752–1762. [Google Scholar] [CrossRef] [Green Version]
- Pinto, A.R.; Ilinykh, A.; Ivey, M.J.; Kuwabara, J.T.; D’Antoni, M.L.; Debuque, R.; Chandran, A.; Wang, L.; Arora, K.; Rosenthal, N.A.; et al. Revisiting cardiac cellular composition. Circ. Res. 2016, 118, 400–409. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dolmatova, E.; Spagnol, G.; Boassa, D.; Baum, J.R.; Keith, K.; Ambrosi, C.; Kontaridis, M.I.; Sorgen, P.L.; Sosinsky, G.E.; Duffy, H.S. Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H1208–H1218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rook, M.B.; Jongsma, H.J.; de Jonge, B. Single channel currents of homo- and heterologous gap junctions between cardiac fibroblasts and myocytes. Pflug. Arch. 1989, 414, 95–98. [Google Scholar] [CrossRef] [PubMed]
- Miragoli, M.; Gaudesius, G.; Rohr, S. Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ. Res. 2006, 98, 801–810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferko, M.; Andelova, N.; Szeiffova Bacova, B.; Jasova, M. Myocardial adaptation in pseudohypoxia: Signaling and regulation of mPTP via mitochondrial connexin 43 and cardiolipin. Cells 2019, 8, 1449. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lemieux, H.; Hoppel, C.L. Mitochondria in the human heart. J. Bioenerg. Biomembr. 2009, 41, 99–106. [Google Scholar] [CrossRef] [Green Version]
- Halestrap, A.P. Mitochondria and preconditioning: A connexin connection? Circ. Res. 2006, 99, 10–12. [Google Scholar] [CrossRef] [Green Version]
- Opie, L.H.; Sack, M.N. Metabolic plasticity and the promotion of cardiac protection in ischemia and ischemic preconditioning. J. Mol. Cell. Cardiol. 2002, 34, 1077–1089. [Google Scholar] [CrossRef]
- Boengler, K.; Dodoni, G.; Rodriguez-Sinovas, A.; Cabestrero, A.; Ruiz-Meana, M.; Gres, P.; Konietzka, I.; Lopez-Iglesias, C.; Garcia-Dorado, D.; Di Lisa, F.; et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc. Res. 2005, 67, 234–244. [Google Scholar] [CrossRef] [Green Version]
- Boengler, K.; Schulz, R. Connexin 43 and mitochondria in cardiovascular health and disease. Adv. Exp. Med. Biol. 2017, 982, 227–246. [Google Scholar] [CrossRef]
- Kavazis, A.N.; Alvarez, S.; Talbert, E.; Lee, Y.; Powers, S.K. Exercise training induces a cardioprotective phenotype and alterations in cardiac subsarcolemmal and intermyofibrillar mitochondrial proteins. Am. J. Physiol. Heart Circ. Physiol. 2009, 297, H144–H152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kavazis, A.N.; McClung, J.M.; Hood, D.A.; Powers, S.K. Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli. Am. J. Physiol. Heart Circ. Physiol. 2008, 294, H928–H935. [Google Scholar] [CrossRef] [PubMed]
- Holmuhamedov, E.L.; Oberlin, A.; Short, K.; Terzic, A.; Jahangir, A. Cardiac subsarcolemmal and interfibrillar mitochondria display distinct responsiveness to protection by diazoxide. PLoS ONE 2012, 7, e44667. [Google Scholar] [CrossRef] [PubMed]
- Boengler, K.; Stahlhofen, S.; van de Sand, A.; Gres, P.; Ruiz-Meana, M.; Garcia-Dorado, D.; Heusch, G.; Schulz, R. Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria. Basic Res. Cardiol. 2009, 104, 141–147. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez-Sinovas, A.; Ruiz-Meana, M.; Denuc, A.; Garcia-Dorado, D. Mitochondrial Cx43, an important component of cardiac preconditioning. Biochim. Biophys. Acta Biomembr. 2018, 1860, 174–181. [Google Scholar] [CrossRef]
- Rodriguez-Sinovas, A.; Boengler, K.; Cabestrero, A.; Gres, P.; Morente, M.; Ruiz-Meana, M.; Konietzka, I.; Miro, E.; Totzeck, A.; Heusch, G.; et al. Translocation of connexin 43 to the inner mitochondrial membrane of cardiomyocytes through the heat shock protein 90-dependent TOM pathway and its importance for cardioprotection. Circ. Res. 2006, 99, 93–101. [Google Scholar] [CrossRef]
- Ruiz-Meana, M.; Rodriguez-Sinovas, A.; Cabestrero, A.; Boengler, K.; Heusch, G.; Garcia-Dorado, D. Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 2008, 77, 325–333. [Google Scholar] [CrossRef]
- Miro-Casas, E.; Ruiz-Meana, M.; Agullo, E.; Stahlhofen, S.; Rodriguez-Sinovas, A.; Cabestrero, A.; Jorge, I.; Torre, I.; Vazquez, J.; Boengler, K.; et al. Connexin43 in cardiomyocyte mitochondria contributes to mitochondrial potassium uptake. Cardiovasc. Res. 2009, 83, 747–756. [Google Scholar] [CrossRef] [Green Version]
- Soetkamp, D.; Nguyen, T.T.; Menazza, S.; Hirschhauser, C.; Hendgen-Cotta, U.B.; Rassaf, T.; Schluter, K.D.; Boengler, K.; Murphy, E.; Schulz, R. S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function. Basic Res. Cardiol. 2014, 109, 433. [Google Scholar] [CrossRef] [Green Version]
- Trudeau, K.; Muto, T.; Roy, S. Downregulation of mitochondrial connexin 43 by high glucose triggers mitochondrial shape change and cytochrome C release in retinal endothelial cells. Investig. Ophthalmol. Vis. Sci. 2012, 53, 6675–6681. [Google Scholar] [CrossRef] [Green Version]
- Waza, A.A.; Andrabi, K.; Hussain, M.U. Protein kinase C (PKC) mediated interaction between conexin43 (Cx43) and K(+)(ATP) channel subunit (Kir6.1) in cardiomyocyte mitochondria: Implications in cytoprotection against hypoxia induced cell apoptosis. Cell Signal. 2014, 26, 1909–1917. [Google Scholar] [CrossRef]
- Penna, C.; Perrelli, M.G.; Raimondo, S.; Tullio, F.; Merlino, A.; Moro, F.; Geuna, S.; Mancardi, D.; Pagliaro, P. Postconditioning induces an anti-apoptotic effect and preserves mitochondrial integrity in isolated rat hearts. Biochim. Biophys. Acta 2009, 1787, 794–801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tu, R.H.; Li, Q.J.; Huang, Z.; He, Y.; Meng, J.J.; Zheng, H.L.; Zeng, Z.Y.; Zhong, G.Q. Novel functional role of heat shock protein 90 in mitochondrial connexin 43-mediated hypoxic postconditioning. Cell. Physiol. Biochem. 2017, 44, 982–997. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martins-Marques, T.; Anjo, S.I.; Pereira, P.; Manadas, B.; Girao, H. Interacting network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is modulated by ischemia and reperfusion in the heart. Mol. Cell. Proteom. 2015, 14, 3040–3055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Agullo-Pascual, E.; Lin, X.; Leo-Macias, A.; Zhang, M.; Liang, F.X.; Li, Z.; Pfenniger, A.; Lubkemeier, I.; Keegan, S.; Fenyo, D.; et al. Super-resolution imaging reveals that loss of the C-terminus of connexin43 limits microtubule plus-end capture and NaV1.5 localization at the intercalated disc. Cardiovasc. Res. 2014, 104, 371–381. [Google Scholar] [CrossRef] [PubMed]
- Kieken, F.; Mutsaers, N.; Dolmatova, E.; Virgil, K.; Wit, A.L.; Kellezi, A.; Hirst-Jensen, B.J.; Duffy, H.S.; Sorgen, P.L. Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circ. Res. 2009, 104, 1103–1112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Smyth, J.W.; Zhang, S.S.; Sanchez, J.M.; Lamouille, S.; Vogan, J.M.; Hesketh, G.G.; Hong, T.; Tomaselli, G.F.; Shaw, R.M. A 14-3-3 mode-1 binding motif initiates gap junction internalization during acute cardiac ischemia. Traffic 2014, 15, 684–699. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Sun, L.; Xuan, L.; Pan, Z.; Hu, X.; Liu, H.; Bai, Y.; Jiao, L.; Li, Z.; Cui, L.; et al. Long non-coding RNA CCRR controls cardiac conduction via regulating intercellular coupling. Nat. Commun. 2018, 9, 4176. [Google Scholar] [CrossRef] [Green Version]
- Martins-Marques, T.; Catarino, S.; Goncalves, A.; Miranda-Silva, D.; Goncalves, L.; Antunes, P.; Coutinho, G.; Leite Moreira, A.; Falcao Pires, I.; Girao, H. EHD1 modulates Cx43 gap junction remodeling associated with cardiac diseases. Circ. Res. 2020, 126, e97–e113. [Google Scholar] [CrossRef]
- Lissoni, A.; Hulpiau, P.; Martins-Marques, T.; Wang, N.; Bultynck, G.; Schulz, R.; Witschas, K.; Girao, H.; De Smet, M.; Leybaert, L. RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes. Cardiovasc. Res. 2019. [Google Scholar] [CrossRef]
- Basheer, W.A.; Xiao, S.; Epifantseva, I.; Fu, Y.; Kleber, A.G.; Hong, T.; Shaw, R.M. GJA1-20k arranges actin to guide Cx43 delivery to cardiac intercalated discs. Circ. Res. 2017, 121, 1069–1080. [Google Scholar] [CrossRef] [PubMed]
- Xiao, S.; Shimura, D.; Baum, R.; Hernandez, D.M.; Agvanian, S.; Nagaoka, Y.; Katsumata, M.; Lampe, P.D.; Kleber, A.G.; Hong, T.; et al. Auxiliary trafficking subunit GJA1-20k protects Connexin43 from degradation and limits ventricular arrhythmias. J. Clin. Investig. 2020. [Google Scholar] [CrossRef] [PubMed]
- Martins-Marques, T.; Catarino, S.; Marques, C.; Matafome, P.; Ribeiro-Rodrigues, T.; Baptista, R.; Pereira, P.; Girao, H. Heart ischemia results in connexin43 ubiquitination localized at the intercalated discs. Biochimie 2015, 112, 196–201. [Google Scholar] [CrossRef]
- Martins-Marques, T.; Catarino, S.; Zuzarte, M.; Marques, C.; Matafome, P.; Pereira, P.; Girao, H. Ischaemia-induced autophagy leads to degradation of gap junction protein connexin43 in cardiomyocytes. Biochem. J. 2015, 467, 231–245. [Google Scholar] [CrossRef] [Green Version]
- Bejarano, E.; Yuste, A.; Patel, B.; Stout, R.F., Jr.; Spray, D.C.; Cuervo, A.M. Connexins modulate autophagosome biogenesis. Nat. Cell Biol. 2014, 16, 401–414. [Google Scholar] [CrossRef] [PubMed]
- Davidson, S.M.; Andreadou, I.; Barile, L.; Birnbaum, Y.; Cabrera-Fuentes, H.A.; Cohen, M.V.; Downey, J.M.; Girao, H.; Pagliaro, P.; Penna, C.; et al. Circulating blood cells and extracellular vesicles in acute cardioprotection. Cardiovasc. Res. 2019, 115, 1156–1166. [Google Scholar] [CrossRef] [PubMed]
- Batista-Almeida, D.; Martins-Marques, T.; Ribeiro-Rodrigues, T.; Girao, H. The role of proteostasis in the regulation of cardiac intercellular communication. Adv. Exp. Med. Biol. 2020, 1233, 279–302. [Google Scholar] [CrossRef]
- Martins-Marques, T.; Pinho, M.J.; Zuzarte, M.; Oliveira, C.; Pereira, P.; Sluijter, J.P.; Gomes, C.; Girao, H. Presence of Cx43 in extracellular vesicles reduces the cardiotoxicity of the anti-tumour therapeutic approach with doxorubicin. J. Extracell. Vesicles 2016, 5, 32538. [Google Scholar] [CrossRef]
- Soares, A.R.; Martins-Marques, T.; Ribeiro-Rodrigues, T.; Ferreira, J.V.; Catarino, S.; Pinho, M.J.; Zuzarte, M.; Isabel Anjo, S.; Manadas, B.; Sluijter, J.P.G.; et al. Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci. Rep. 2015, 5, 13243. [Google Scholar] [CrossRef] [Green Version]
- Almeida Paiva, R.; Martins-Marques, T.; Jesus, K.; Ribeiro-Rodrigues, T.; Zuzarte, M.; Silva, A.; Reis, L.; da Silva, M.; Pereira, P.; Vader, P.; et al. Ischaemia alters the effects of cardiomyocyte-derived extracellular vesicles on macrophage activation. J. Cell. Mol. Med. 2019, 23, 1137–1151. [Google Scholar] [CrossRef] [Green Version]
- Ribeiro-Rodrigues, T.M.; Laundos, T.L.; Pereira-Carvalho, R.; Batista-Almeida, D.; Pereira, R.; Coelho-Santos, V.; Silva, A.P.; Fernandes, R.; Zuzarte, M.; Enguita, F.J.; et al. Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis. Cardiovasc. Res. 2017, 113, 1338–1350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laird, D.W.; Puranam, K.L.; Revel, J.P. Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem. J. 1991, 273 Pt 1, 67–72. [Google Scholar] [CrossRef] [Green Version]
- Montgomery, J.; Ghatnekar, G.S.; Grek, C.L.; Moyer, K.E.; Gourdie, R.G. Connexin 43-based therapeutics for dermal wound healing. Int. J. Mol. Sci. 2018, 19, 1778. [Google Scholar] [CrossRef] [Green Version]
- Willebrords, J.; Crespo Yanguas, S.; Maes, M.; Decrock, E.; Wang, N.; Leybaert, L.; Kwak, B.R.; Green, C.R.; Cogliati, B.; Vinken, M. Connexins and their channels in inflammation. Crit. Rev. Biochem. Mol. Biol. 2016, 51, 413–439. [Google Scholar] [CrossRef] [PubMed]
- Becker, D.L.; Phillips, A.R.; Duft, B.J.; Kim, Y.; Green, C.R. Translating connexin biology into therapeutics. Semin. Cell Dev. Biol. 2016, 50, 49–58. [Google Scholar] [CrossRef] [PubMed]
- Dhein, S.; Manicone, N.; Muller, A.; Gerwin, R.; Ziskoven, U.; Irankhahi, A.; Minke, C.; Klaus, W. A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. A mapping study. Naunyn Schmiedebergs Arch. Pharmacol. 1994, 350, 174–184. [Google Scholar] [CrossRef] [PubMed]
- Pedersen, C.M.; Venkatasubramanian, S.; Vase, H.; Hyldebrandt, J.A.; Contractor, H.; Schmidt, M.R.; Botker, H.E.; Cruden, N.L.; Newby, D.E.; Kharbanda, R.K.; et al. Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury. Br. J. Clin. Pharmacol. 2016, 81, 1037–1045. [Google Scholar] [CrossRef]
- Skyschally, A.; Walter, B.; Schultz Hansen, R.; Heusch, G. The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs. Naunyn Schmiedebergs Arch. Pharmacol. 2013, 386, 383–391. [Google Scholar] [CrossRef]
- Boengler, K.; Bulic, M.; Schreckenberg, R.; Schluter, K.D.; Schulz, R. The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture following ischaemia/reperfusion independent from mitochondrial connexin 43. Br. J. Pharmacol. 2017, 174, 2060–2073. [Google Scholar] [CrossRef]
- Engstrom, T.; Nepper-Christensen, L.; Helqvist, S.; Klovgaard, L.; Holmvang, L.; Jorgensen, E.; Pedersen, F.; Saunamaki, K.; Tilsted, H.H.; Steensberg, A.; et al. Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: A phase 2 randomised clinical trial. Heart 2018, 104, 1593–1599. [Google Scholar] [CrossRef] [Green Version]
- Hunter, A.W.; Barker, R.J.; Zhu, C.; Gourdie, R.G. Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol. Biol. Cell 2005, 16, 5686–5698. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rhett, J.M.; Jourdan, J.; Gourdie, R.G. Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol. Biol. Cell 2011, 22, 1516–1528. [Google Scholar] [CrossRef] [PubMed]
- Ghatnekar, G.S.; Grek, C.L.; Armstrong, D.G.; Desai, S.C.; Gourdie, R.G. The effect of a connexin43-based Peptide on the healing of chronic venous leg ulcers: A multicenter, randomized trial. J. Investig. Dermatol. 2015, 135, 289–298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grek, C.L.; Prasad, G.M.; Viswanathan, V.; Armstrong, D.G.; Gourdie, R.G.; Ghatnekar, G.S. Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: A multicenter, randomized trial. Wound Repair Regen. 2015, 23, 203–212. [Google Scholar] [CrossRef] [PubMed]
- Grek, C.L.; Montgomery, J.; Sharma, M.; Ravi, A.; Rajkumar, J.S.; Moyer, K.E.; Gourdie, R.G.; Ghatnekar, G.S. A multicenter randomized controlled trial evaluating a Cx43-mimetic peptide in cutaneous scarring. J. Investig. Dermatol. 2017, 137, 620–630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brisset, A.C.; Isakson, B.E.; Kwak, B.R. Connexins in vascular physiology and pathology. Antioxid. Redox Signal. 2009, 11, 267–282. [Google Scholar] [CrossRef]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Rusiecka, O.M.; Montgomery, J.; Morel, S.; Batista-Almeida, D.; Van Campenhout, R.; Vinken, M.; Girao, H.; Kwak, B.R. Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection. Biomolecules 2020, 10, 1225. https://doi.org/10.3390/biom10091225
Rusiecka OM, Montgomery J, Morel S, Batista-Almeida D, Van Campenhout R, Vinken M, Girao H, Kwak BR. Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection. Biomolecules. 2020; 10(9):1225. https://doi.org/10.3390/biom10091225
Chicago/Turabian StyleRusiecka, Olga M., Jade Montgomery, Sandrine Morel, Daniela Batista-Almeida, Raf Van Campenhout, Mathieu Vinken, Henrique Girao, and Brenda R. Kwak. 2020. "Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection" Biomolecules 10, no. 9: 1225. https://doi.org/10.3390/biom10091225