Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial

Engstrøm, Thomas; Nepper‐Christensen, Lars; Helqvist, Steffen; Kløvgaard, Lene; Holmvang, Lene; Jørgensen, Erik; Pedersen, Frants; Saunamäki, Kari; Tilsted, Hans Henrik; Steensberg, Adam; Fabricius, Søren; Mouritzen, Ulrik; Vejlstrup, Niels; Ahtarovski, Kiril Aleksov; Göransson, Christoffer; Bertelsen, Litten; Kyhl, Kasper; Olivecrona, Göran; Kelbæk, Henning; Lassen, Jens Flensted; Køber, Lars; Lønborg, Jacob

doi:10.1136/heartjnl-2017-312774

Cited by 25 publications

(21 citation statements)

References 22 publications

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“…These cardioprotective effects, however, appeared independent of mitoCx43 [139]. Finally, a clinical proof-of-concept Phase II study on 585 patients with ST-segment elevation myocardial infarction (STEMI) showed that danegaptide, administered at least 10 min prior to reperfusion, did not improve myocardial salvage [140].…”

Section: Concluding Remarks: On the Way Towards Cx43-targeted Strategmentioning

confidence: 99%

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

et al. 2020

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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.

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Section: Concluding Remarks: On the Way Towards Cx43-targeted Strategmentioning

confidence: 99%

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

et al. 2020

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“…Finally, the dipeptide ZP1609 (danegaptide) has antiarrhythmic properties and has been shown to reduce infarct size following ischemia/ reperfusion in pigs [96]. Nevertheless, this GJ coupling-modulating peptide failed to improve myocardial salvage in patients with ST-elevation myocardial infarction (STEMI) in a Phase II randomized clinical trial [97]. It is promising that multiple tools interfering with Cx43 expression, its interactome, or channel function have appeared in recent years, yet many questions still need to be addressed regarding their exact working mechanisms as well as their specificity and stability in organisms.…”

Section: Therapeutic Strategies Targeting Cx43mentioning

confidence: 99%

Biological Functions of Connexin43 Beyond Intercellular Communication

Martins‐Marques

Ribeiro-Rodrigues

Batista-Almeida

et al. 2019

Trends in Cell Biology

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Connexin43 (Cx43) is commonly associated with direct cell-cell communication through gap junctions (GJs). However, recent groundbreaking studies have challenged this dogma, implicating Cx43 in other biological processes, such as transcription, metabolism, autophagy, and ion channel trafficking. How Cx43 participates in these processes remains largely unknown, although its high turnover rate, capacity to bind to myriad proteins, and the discovery of truncated isoforms of Cx43, ascribe to this protein unanticipated roles in chief processes that require fine-tuned regulation. Accordingly, Cx43 can be regarded as a central integrative hub to which diverse cues converge to be processed in a concerted manner. In this review, we examine the noncanonical roles of Cx43 and discuss the implications of these functions in human diseases and future therapeutic strategies. A Second Life for an Old-Fashioned Protein: The Role of Cx43 Beyond Gap Junction Communication Channel-forming connexin proteins are canonically associated with gap junction (GJ)-mediated communication between adjacent cells, ensuring both metabolic and electrical coupling, fundamental for tissue and organ homeostasis (Box 1). As a result, GJ-mediated intercellular communication (GJIC) has been the main focus in the connexin field over the past 30 years. However, emerging evidence has ascribed unanticipated biological roles to connexins that go beyond direct intercellular communication, pointing towards broader functions of these membrane proteins. For example, unbiased proteomic approaches of Connexin43 (Cx43), have revealed a long list of binding proteins related to various biological processes and mechanisms. Moreover, the presence of Cx43 in intracellular compartments, including the nucleus and mitochondria, has been reported. Several studies have unveiled these noncanonical functions in detail, associating Cx43 with features such as gene transcription, development, mitochondrial homeostasis, autophagy (see Glossary) regulation, intracellular trafficking, and long-distance communication mediated by extracellular vesicles (EVs). Here, we present an integrated overview of the recent literature that has revealed unforeseen functions for connexins, with a particular focus on Cx43. In fact, Cx43 is the most ubiquitously distributed family member, expressed in multiple cell types across almost all tissues and organs. This has favored its study as a model for other connexins. Most of the differential features attributed to each connexin family member have been related to the size and variability of their intracellular loop and C terminus [1]. In agreement, many of the noncanonical roles of Cx43 have been ascribed to its cytosolic C-terminal tail constituting a preferential platform to accommodate diverse protein-protein interactions. Given its unusual versatility and short half-life, it is conceivable that the evolutionary selection of Cx43 as the predominant connexin isoform in mammals makes it a preferential protein to exhibit biological functions beyond GJIC...

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“…However, a recently published phase II study did not confirm the early results. 27 Other enhancers of GJ function such as ACT1, a peptide that mimics the carboxyl terminus of Cx43, have been evaluated in cutaneous ulcers 28 and arrhythmias, where they led to wound re-epithelialization and reduced inducible arrhythmias following ventricular injury, respectively. 29 Conversely, strategies that target specific Cxs with antisense oligonucleotide and mimetic peptides can be used if the goal is to block intercellular communication.…”

Section: Modulators Of Gj Function and Targeting In Diseases Outside mentioning

confidence: 99%

Gap junctions in liver disease: Implications for pathogenesis and therapy

Hernández‐Guerra

Hadjihambi

Jalan

2019

Journal of Hepatology

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In the normal liver, cells interact closely through gap junctions. By providing a pathway for the trafficking of low molecular mass molecules, these channels contribute to tissue homeostasis and maintenance of hepatic function. Thus, dysfunction of gap junctions affects a wide variety of liver processes, such as differentiation, cell death, inflammation and fibrosis. In fact, dysfunctional gap junctions have been implicated, for more than a decade, in cholestatic disease, hepatic cancer and cirrhosis. Additionally, in recent years there is an increasing body of evidence that these channels are also involved in other relevant and prevalent liver pathological processes, such as non-alcoholic fatty liver disease, acute liver injury and portal hypertension. In parallel to these new clinical implications the available data include controversial observations. Thus, a comprehensive overview is required to better understand the functional complexity of these pores. This paper will review the most recent knowledge concerning gap junction dysfunction, with a special focus on the role of these channels in the pathogenesis of relevant clinical entities and on potential therapeutic targets that are amenable to modification by drugs.

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Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial

Abstract: NCT01977755; Pre-results.

Cited by 25 publications

References 22 publications

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

Biological Functions of Connexin43 Beyond Intercellular Communication

Gap junctions in liver disease: Implications for pathogenesis and therapy

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