Search Results (564)

Over the past four decades, cardioprotective research has revealed an extraordinary complexity of cellular and molecular mechanisms capable of mitigating ischemia/reperfusion injury (IRI). Among these, ischemic conditioning has emerged as one of the most influential discoveries: brief episodes of ischemia followed by reperfusion activate protective programs that reduce myocardial damage. These effects can be elicited locally (pre- or postconditioning) or remotely (remote conditioning), acting mainly through paracrine signaling and mitochondria-linked kinase pathways, with both early and delayed windows of protection. We have contributed to clarifying the roles of mitochondria, oxidative stress, prosurvival kinases, connexins, extracellular vesicles, and sterile inflammation, particularly via activation of the NLRP3 inflammasome. Despite robust preclinical evidence, clinical translation of these approaches has remained disappointing. The challenges largely stem from experimental models that poorly reflect real-world clinical settings—such as advanced age, comorbidities, and multidrug therapy—as well as the reliance on surrogate endpoints that do not reliably predict clinical outcomes. Nevertheless, interest in multi-target protective strategies remains strong. New lines of investigation are focusing on emerging mediators—such as gasotransmitters, extracellular vesicles, and endogenous peptides—as well as targeted modulation of inflammatory responses. Future perspectives point toward personalized cardioprotection tailored to patient metabolic and immune profiles, with special attention to high-risk populations in whom IRI continues to represent a major clinical challenge. Full article

Heart-specific overexpression of transcriptional regulator JDP2 (jun dimerization protein 2) for 5 weeks provokes paroxysmal atrial fibrillation (AF) in mice. We now investigated whether AF and atrial remodeling will be reversible upon termination of JDP2 overexpression, and whether paroxysmal AF converts to permanent AF in the presence of maintained JDP2 overexpression. Cardiac-specific JDP2 overexpression for 5 weeks, resulting in paroxysmal AF, was either continued or repressed via a tet-off system for another 5 weeks. ECGs were recorded weekly. Thereafter, heart and lung weights, and atrial mRNA and protein expression were determined. Extending JDP2 overexpression did not aggravate the AF phenotype, still paroxysmal AF, prolongation of PQ intervals, and atrial hypertrophy were present. This phenotype was completely reversible upon cessation of JDP2 overexpression. A massive downregulation of connexin40 and calcium handling proteins, including SERCA2a, calsequestrin, and ryanodine receptor, was observed in atria after prolonged JDP2 overexpression. In conclusion, atrial remodeling and paroxysmal AF under JDP2 overexpression are not sufficient to maintain or aggravate AF in the absence of JDP2. The comparison of the two groups indicates that the downregulation of calcium proteins and connexins is an important factor in the maintenance of the disease. Full article

Patients with ulcerative colitis exhibit an increased risk for supraventricular arrhythmia during the active disease phase of the disease and show signs of atrial electrophysiological remodeling in remission. The goal of this study was to determine the basis for colitis-induced changes in atrial excitability. In a mouse model (C57BL/6; 3 months) of dextran sulfate sodium (DSS)-induced active colitis (3.5% weight/volume, 7 days), electrocardiograms (ECG) revealed altered atrial electrophysiological properties with a prolonged P-wave duration and PR interval. ECG changes coincided with a decreased atrial conduction velocity in Langendorff perfused hearts. Action potentials (AP) recorded from isolated atrial myocytes displayed an attenuated maximal upstroke velocity and amplitude during active colitis, as well as a prolonged AP duration (APD). Voltage clamp analysis revealed a colitis-induced shift in the voltage-dependent activation of the Na-current (I_Na) to more depolarizing voltages. In addition, protein levels of Na_v1.5 protein and connexin isoform Cx43 were reduced. APD prolongation depended on a reduction in the transient outward K-current (I_to) mostly generated by K_v4.2 channels. The changes in ECG, atrial conductance, and APD were reversible upon remission. The change in conduction velocity predominantly depended on the reversibility of the reduced Cx43 and Na_v1.5 expression. Treatment of mice with inhibitors of Angiotensin-converting enzyme (ACE) or Angiotensin II (AngII) receptor type 1 (AT1R) prevented the colitis-induced atrial electrophysiological remodeling. Our data support a colitis-induced increase in AngII signaling that promotes atrial electrophysiological remodeling and puts colitis patients at an increased risk for atrial arrhythmia. Full article

Background: Kölliker’s organ (KO), a transient structure in the cochlea, plays a critical role in the auditory maturation of mammals, particularly during embryonic and early postnatal development. This organ is essential for the proper differentiation and function of cochlear cells, acting as a pivotal source of signalling molecules that influence hair cell development and synaptic connectivity. Methods: This study systematically analyses the literature according to the PRISMA statement in order to evaluate the function roles of KO during cochlea development, reporting the molecular mechanisms and signalling pathways involved. Results: From our study, it emerged that KO supporting cells release adenosine triphosphate (ATP) through connexin hemichannels, initiating a cascade of intracellular calcium (Ca²⁺) signalling in adjacent inner hair cells (IHCs). This signalling promotes the release of glutamate, facilitating synaptic excitation of afferent nerve fibres and enhancing auditory neuron maturation prior to the onset of hearing. Additionally, the spontaneous electrical activity generated within KO supports the establishment of essential neural connections in the auditory pathway. The dynamic interplay between ATP release, Ca²⁺ signalling, and morphological changes in KO is crucial for cochlear compartmentalisation and fluid regulation, contributing to the formation of endolymph and perilymph. Furthermore, KO supports cellular plasticity and may provide a reservoir of precursor cells capable of trans-differentiating into hair cells under specific conditions. Conclusions: Dysregulation of KO function or delayed degeneration of its supporting cells has been implicated in auditory disorders, underscoring the importance of this organ in normal cochlear development and auditory function. Despite its identification over a century ago, further investigation is necessary to elucidate the molecular mechanisms underlying KO’s contributions to auditory maturation, particularly in human physiology. Full article

A part of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is caused by mutant CHRNA4. The pathomechanisms underlying motor seizures followingly brief/sudden awakening (paroxysmal arousal) in ADSHE seizures remain to be clarified. This study determined extracellular levels of ACh and L-glutamate in the pedunculopontine nucleus (PPN) and its projection regions, including the thalamus and basal ganglia, during wakefulness, slow-wave sleep (SWS) and paroxysmal arousal of transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG), corresponding to human S284L-mutant CHRNA4, using microdialysis. The expression of connexin43 and pannexin1 in the plasma membrane of the PPN was determined using capillary immunoblotting. The expressions of connexin43 and pannexin1 in the PPN plasma membrane of S286L-TG were larger than the wild type. The extracellular L-glutamate levels in the PPN and projection regions of S286L-TG consistently increased during both wakefulness and SWS compared to the wild type. The extracellular levels of ACh and L-glutamate in the PPN and projection regions decreased accompaning SWS in the wild type. In S286L-TG, this decreasing extracellular ACh level was observed, whereas decreasing L-glutamate level was impaired. Both extracellular levels of ACh and L-glutamate in the PPN and projection regions drastically increased during paroxysmal arousal. Hemichannel inhibitors suppressed the increasing releases of ACh and L-glutamate induced by paroxysmal arousal but decreased and did not affect extracellular levels of L-glutamate and ACh during wakefulness and SWS, respectively. In particular, under hemichannels inhibition, decreasing L-glutamate release accompanying SWS was observed in S286L-TG. This study elucidated that enhanced hemichannels are predominantly involved in the dysfunction of glutamatergic transmission compared to AChergic transmission during the interictal stage in S286L-TG, whereas the hyperactivation of hemichannels contributes to the generation of paroxysmal arousal. Therefore, the hyperactivated excitatory tripartite synaptic transmission associated with hemichannels in the PPN and projection regions plays important roles in epileptogenesis/ictogenesis in S286L-TG. Full article

Endothelial progenitor cells (EPC) are considered to support neovascularization and endothelial repair by being incorporated into newly formed or injured vessels and by improving vascularization in a paracrine manner by secreting proangiogenic factors. Here, we studied the role of gap junctional communication between EPC and endothelial cells in long-term co-cultures in vitro. The cultivation of endothelial cells together with mouse embryonic EPC (E 7.5) induced the spontaneous formation of angiogenic networks after 3–6 days consisting of both cell types, but not in the respective monocultures, whereas their respective cultivation on a basement matrix induced the formation of tube-like structures, as expected. The angiogenic network formation could not be mimicked by the incubation of endothelial cells with supernatants of EPC only. We therefore hypothesized that direct interaction and cell-cell communication is required to induce the angiogenic network formation in co-cultures with endothelial cells. Expression analysis demonstrated expression of the gap junctional protein connexin 43 (Cx43) in EPC. Moreover, dye injection studies as well as FACS analysis identified gap junctional communication between endothelial cells and EPC. The inhibition of gap junctions by pharmacological blockers significantly reduced the angiogenic network formation, confirming that gap junctional communication between both cell types is required for this process. Full article

Bone is a highly mechanosensitive tissue, where mechanical signaling plays a central role in maintaining skeletal homeostasis. Mechanotransduction regulates the balance between bone formation and resorption through coordinated interactions among bone cells. Key mechanosensing structures—including the extracellular/pericellular matrix (ECM/PCM), integrins, ion channels, connexins, and primary cilia, translate mechanical cues into biochemical signals that drive bone adaptation. Disruptions in mechanotransduction are increasingly recognized as an important factor in osteoporosis. Under pathological conditions, impaired mechanical signaling reduces bone formation and accelerates bone resorption, leading to skeletal fragility. Defects in mechanotransduction disrupt key pathways involved in bone metabolism, further exacerbating bone loss. Therefore, targeting mechanotransduction presents a promising pharmacological strategy for osteoporosis treatment. Recent advances have focused on developing drugs that enhance bone mechanosensitivity by modulating key mechanotransduction pathways, including integrins, ion channels, connexins, and Wnt signaling. A deeper understanding of mechanosignaling mechanisms may pave the way for novel therapeutic approaches aimed at restoring bone mass, mechanical integrity, and mechanosensitive bone adaptation. Full article

Endometriosis is a complicated condition characterized by inflammation, low oocyte quality, and decreased uterus receptivity, associated with fertility issues. This study aims to better understand the reduced pregnancy outcome in endometriosis by analyzing both the granulosa cells (GCs) and the follicular fluids (FFs) obtained during the assisted reproductive technology (ART)-related oocyte pick-up. Seventy patients, approaching our ART Center with the diagnosis of infertility for Age-Idiopathic Factor (AIF) (n = 36), endometriosis (ENDO) (n = 23), or male factor (MF) (n = 11), were enrolled in this study. GCs from each group were separately analyzed for morphology, replication, and expression of Connexin-43 and Follicle-Stimulating Hormone Receptor (FSHR) by microscopy, flow cytometry, and immunocytochemistry. Results show that FF in a culture medium allowed GCs to survive and replicate. Upon culturing GCs from each group with ENDO follicular fluid, increases were observed in both population doublings and in the development of fibroblast-like and muscle-like morphologies. Despite undergoing morphological changes, GCs consistently expressed FSHR. However, exposure to ENDO follicular fluid led to an upregulation of Connexin-43 expression across all GC groups. These findings suggest that in endometriosis, FF contains unidentified factors that can induce aberrant replication, morphological differentiation, and overexpression of Connexin-43, potentially contributing to follicular dysfunction. Full article

Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with a proliferative advantage, allowing them to rapidly produce energy (in the form of ATP) and generate metabolic intermediates necessary for the biosynthesis of macromolecules essential for cell growth. It is important to understand the role of ion channels in the tumor context since they participate in various physiological processes and in the regulation of the tumor microenvironment. These changes may contribute to the development and transformation of cancer cells, as well as affect the communication between cells and the surrounding microenvironment, including impaired or altered expression and functionality of ion channels. Therefore, the aim of this review is to elucidate the impact of the tumor microenvironment on the electrical properties of the cellular membranes in several cancers as a possible therapeutic target. Full article

Non-coding RNAs (ncRNAs) are sequences that do not encode for proteins and play key roles in different cellular processes, including cell proliferation and differentiation. On the other hand, connexins (Cxs) are transmembrane proteins that principally allow intercellular communication. In pathological conditions such as cancer, there is a deregulation in the expression and/or function of ncRNAs and Cxs, which in turn leads to an enhancement in the aggressive phenotype, such as a greater proliferative and invasive capacity. This suggests a plausible interplay between ncRNAs and Cxs. Based on that, this review aims to summarize the current knowledge regarding this relationship and to analyze how it may influence the development of aggressive traits in cancer cells and the clinicopathological features of cancer patients. Finally, we discuss the potential of ncRNAs and Cxs as promising clinical biomarkers for cancer diagnosis, prognosis, and therapeutic targeting. Full article

In the heart, Connexin 43 (Cx43) is involved in intercellular communication through gap junctions and exosomes. In addition, Cx43-formed hemichannels at the plasma membrane are important for ion homeostasis and cellular volume regulation. Through its localization within nuclei and mitochondria, Cx43 influences the function of the respective organelles. Several cardiovascular diseases such as heart failure, ischemia/reperfusion injury, hypertrophic cardiomyopathy and arrhythmias are characterized by Cx43 downregulation and a dysregulated Cx43 function. Accordingly, a putative therapeutic approach of these diseases would include the induction of Cx43 expression in the damaged heart, albeit such induction may have both beneficial and detrimental effects. In this review we discuss the consequences of increasing cardiac Cx43 expression, and discuss this manipulation as a strategy for the treatment of cardiovascular diseases. Full article

Atherosclerosis, a condition characterized by the accumulation of lipids and a culprit behind cardiovascular events, has long been studied. However, in recent years, there has been an increase in interest in its initiation, with researchers shifting focus from traditional pathways involving the vascular infiltration of oxidized lipids and towards the novel presence of chronic inflammatory pathways. The accumulation of pro-inflammatory cytokines, in combination with the activation of transcription factors, creates a positive feedback loop that drives the creation and progression of atherosclerosis. From the upregulation of the nod-like receptor protein 3 (NLRP3) inflammasome and the Notch and Wnt pathways to the increased expression of VEGF-A and the downregulation of connexins Cx32, Cx37, and Cx40, these processes contribute further to endothelial dysfunction and plaque formation. Herein, we aim to provide insight into the molecular pathways and mechanisms implicated in the initiation and progression of atherosclerotic plaques, and to review the risk factors associated with their development. Full article

Pulmonary hypertension (PH) is a complex condition characterized by pulmonary artery constriction and vascular remodeling. Connexin 43 (Cx43), involved in cellular communication, may play a role in PH development. Cx43 heterozygous (Cx43^+/−) mice show partial protection against hypoxia-induced pulmonary remodeling, with prior research highlighting its role in rat pulmonary artery fibroblast (PAF) proliferation and migration. However, inhibiting Cx43 may compromise nitric oxide (NO)-mediated vascular relaxation. This study evaluated the effects of Cx43 on mouse PAF (MPAF) proliferation, migration, NO-dependent and independent pulmonary vascular relaxation, and NO synthesis. Proliferation and migration were assessed in Cx43^+/− MPAFs under normoxic and hypoxic conditions. Vascular responses were analyzed in intra-lobar pulmonary artery rings with acetylcholine (ACh), SNAP, and U46619, while NO production was measured in lung tissue. Both genetic knockdown and pharmacological inhibition of Cx43 significantly reduced serum-induced proliferation but not migration under normoxia, while ^37,43Gap27 inhibited hypoxia-induced proliferation and migration. The effects of genetic knockdown and pharmacological inhibition of Cx43 on vascular reactivity were also investigated. NO-dependent and independent relaxations and NO production were reduced in Cx43^+/− mice by ^37,43Gap27. In conclusion, while Cx43 inhibition may protect against PAF proliferation and migration, it could also impair pulmonary vascular relaxation, at least in part through a reduction in NO signaling. Further studies are needed to fully understand the mechanisms by which Cx43 influences NO signaling. Full article

Oral squamous cell carcinoma (OSCC) is the main form of head and neck cancer. Gap junctions (GJs) are communication channels involved in cell proliferation control; they consist of hemichannels formed by connexin (Cx) proteins. The abnormal expression/function of Cx43 has been associated with tumor progression. Also, some human papillomaviruses (HPVs) have been linked to squamous cell cancer. Therefore, this study aimed at assessing Cx43 as a potential OSCC biomarker and exploring its association with histopathological differentiation and HPV infection. OSCC samples were inspected using hematoxylin and eosin staining, and Cx43 expression and HPV 16/18 were tested by immunofluorescence. Pearson correlation tests, ANOVA, and Kaplan–Meier curves were used in the analysis. Samples from 39 patients with OSCC were studied. Most had well-differentiated histology and 61.5% were HPV+. Cx43 expression was significantly associated with HPV infection (p = 0.047), differentiation (p < 0.001), and survival (p = 0.009), and HPV positivity was also associated with the degree of differentiation (p = 0.012). Cx43 shows potential as a prognostic biomarker for OSCC. Lower Cx43 expression, correlated with poorer differentiation, is associated with an unfavorable prognosis. Further studies are needed to confirm its clinical utility. Full article

The Connexin43 transmembrane protein (Cx43), encoded by the GJA1 gene, is a member of a multigenic family of proteins that oligomerize to form hemichannels and intercellular channels, allowing gap junctional intercellular communication between adjacent cells or communication between the intracellular and extracellular compartments. Cx43 has long been shown to play a significant but complex role in cancer development, acting as a tumor suppressor and/or tumor promoter. The effects of Cx43 are associated with both channel-dependent and -independent functionalities and differ depending on the expression level, subcellular location and the considered stage of cancer progression. Recently, six isoforms of Cx43 have been described and one of them, called GJA1-20k, has also been found to be expressed in cancer cells. This isoform is generated by alternative translation and corresponds to the end part of the fourth transmembrane domain and the entire carboxyl-terminal (CT) domain. Initial studies in the cardiac model implicated GJA1-20k in the trafficking of full-length Cx43 to the plasma membrane, in cytoskeletal dynamics and in mitochondrial fission and subcellular distribution. As these processes are associated with cancer progression, a potential link between Cx43 functions, mitochondrial activity and GJA1-20k expression can be postulated in this context. This review synthetizes the current knowledge on GJA1-20k and its potential involvement in processes related to epithelial-to-mesenchymal transition (EMT) and the proliferation, dissemination and quiescence of cancer cells. Particular emphasis is placed on the putative roles of GJA1-20k in full-length Cx43 exportation to the plasma membrane, mitochondrial activity and functions originally attributed to the CT domain. Full article