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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intercellular communication through gap junctions is essential for the regulation of normal cellular processes. In the diseased state, however, gap junctions may be decreased, inappropriately expressed, or constitutively expressed in either the open or closed state. Thus, it may prove important to develop therapeutic agents to either induce or prevent channel closure. To address this dilemma, the mechanisms that cause channel gating as well as the structure-function and permeability determinants of connexins provide useful information. Residues in the C-terminal tail of Connexin 43 are implicated as sites for phosphorylation by kinases that directly mediate channel gating as well as binding sites that influence gating properties. Gating of gap junctions by pH, insulin, and other growth factors has also been associated with the C-terminal domain. The rational design of inhibitors to channel gating may prove useful for the development of therapeutic agents to maintain Connexin 43 in the open state, with potential benefits in diseases such as cancer, arrhythmias, and the diabetic lens. Alternatively, modeling approaches to obtain gap junctions that are constitutively closed might be targeted to designing compounds that could potentially occlude the pore. In this case, knowledge of the pore-lining residues, as well as permeability determinants, would be useful for developing connexin-specific inhibitors that may have future therapeutic potential for tumor invasiveness and stroke treatment. Thus, information from existing and future studies may lead to the development of site-directed, specific modulators of gap junction communication with potential implications in the therapeutic treatment of disease.
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PMID:Mutagenic approaches to modifying gap junction phenotype. 1244 96

Human marrow stromal cells (hMSCs) provide functional benefit in rats subjected to stroke. Astrocytes are coupled into a cellular network via gap junction channels, predominantly composed of connexin-43 (Cx43) proteins. Astrocytes are believed to play a vital role in neuroprotection by providing energy substrates to neurons and by regulating the concentrations of K+ and neurotransmitters via gap junctions. We therefore investigated the effect of factors secreted by hMSCs on gap junction intercellular communication (GJIC), expression of Cx43, and phosphorylation of Cx43 in an astrocyte cell culture system. Exposing rat cortical astrocytes to various concentrations of hMSC conditioned medium, we demonstrate that hMSCs produce soluble factors that significantly increase astrocytic GJIC, measured by the scrape-loading dye transfer method. Immunohistochemistry and Western blot showed increased Cx43 expression concomitant with altered GJIC. As the PI3K/Akt signaling pathway has been demonstrated to alter gap junction expression and GJIC, we selectively blocked phosphoinositide 3-kinase (PI3K). Addition of the PI3K inhibitor LY294002 decreased GJIC and Cx43 expression in astrocytes. These inhibitory effects of LY294002 were countered by the addition of hMSC conditioned media. Furthermore, coculturing hMSCs with rat astrocytes increased astrocyte GJIC in a manner dependent upon the hMSC/astrocyte ratio. These findings demonstrate that hMSCs secrete soluble factors that increase GJIC of astrocytes through upregulation of Cx43, and indicate a mechanistic role for PI3K.
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PMID:Human marrow stromal cells enhance connexin43 gap junction intercellular communication in cultured astrocytes. 1588 20

Bone morphogenetic proteins play a key role in astrocytic differentiation. Astrocytes express the gap junctional protein connexin-43, which permits exchange of small molecules in brain and enhances synaptic efficacy. Bone marrow stromal cells produce soluble factors including bone morphogenetic protein 2 and bone morphogenetic protein 4 (bone morphogenetic protein 2/4) in ischemic brain. Here, we tested whether intra-carotid infusion of bone marrow stromal cells promotes synaptophysin expression and neurological functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 h of right middle cerebral artery occlusion. Rats were treated with or without bone marrow stromal cells at 24 h after middle cerebral artery occlusion via intra-arterial injection (n=8/group). A battery of functional tests was performed. Immunostaining of 5-bromo-2-deoxyuridine, Ki67, bone morphogenetic protein 2/4, connexin-43, synaptophysin, glial fibrillary acidic protein, neuronal nuclear antigen, and double staining of 5-bromo-2-deoxyuridine/glial fibrillary acidic protein, 5-bromo-2-deoxyuridine/neuronal nuclear antigen, glial fibrillary acidic protein/bone morphogenetic protein 2/4 and glial fibrillary acidic protein/connexin-43 were employed. Rats treated with bone marrow stromal cells significantly (P<0.05) improved functional recovery compared with the controls. 5-Bromo-2-deoxyuridine and Ki67 positive cells in the ipsilateral subventricular zone were significantly (P<0.05) increased in bone marrow stromal cell treatment group compared with the controls, respectively. Administration of bone marrow stromal cells significantly (P<0.05) promoted the proliferating cell astrocytic differentiation, and increased bone morphogenetic protein 2/4, connexin-43 and synaptophysin expression in the ischemic boundary zone compared with the controls, respectively. Bone morphogenetic protein 2/4 expression correlated with the expression of connexin-43 (r=0.84, P<0.05) and connexin-43 expression correlated with the expression of synaptophysin (r=0.73, P<0.05) in the ischemic boundary zone, respectively. Administration of bone marrow stromal cells via an intra-carotid route increases endogenous brain bone morphogenetic protein 2/4 and connexin-43 expression in astrocytes and promotes synaptophysin expression, which may benefit functional recovery after stroke in rats.
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PMID:Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. 1673 Sep 12

Direct cell-to-cell communication in the heart is maintained via gap junction channels composed of proteins termed connexins. Connexin channels ensure molecular and electrical signals propagation and hence are crucial in myocardial synchronization and heart function. Disease-induced gap junctions remodeling and/or an impairment or even block of intercellular communication due to acute pathological conditions results in derangements of myocardial conduction and synchronization. This is critical in the development of both ventricular fibrillation, which is a major cause of sudden cardiac death and persistent atrial fibrillation, most common arrhythmia in clinical practice often resulting in stroke. Many studies suggest that alterations in topology (remodeling), expression, phosphorylation and particularly function of connexin channels due to age or disease are implicated in the development of these life-threatening arrhythmias. It seems therefore challenging to examine whether compounds that could prevent or attenuate gap junctions remodeling and connexin channels dysfunction can protect the heart against arrhythmias that cause sudden death in humans. This assumption is supported by very recent findings showing that an increase of gap junctional conductance by specific peptides can prevents atrial conduction slowing or re-entrant ventricular tachycardia in ischemic heart. Suppression of ischemia-induced dephosphorylation of connexin seems to be one of the mechanisms involved. Another approach for identifying novel treatments is based on the hypothesis that even non-antiarrhythmic drugs with antiarrhythmic ability can modulate gap junctional communication and hence attenuate arrhythmogenic substrates.
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PMID:Myocardial gap junctions: targets for novel approaches in the prevention of life-threatening cardiac arrhythmias. 1837 98

Reproductive hormones have been demonstrated to modulate both gap and tight junction protein expression in the ovary and other reproductive tissues, however the effects of changes in reproductive hormones on the selective permeability of the blood-brain barrier (BBB) remain unclear. Age-related declines in BBB integrity correlate with the loss of serum sex steroids and increase in gonadotropins with menopause/andropause. To examine the effect of reproductive senescence on BBB permeability and gap and tight junction protein expression/localization, female mice at 3 months of age were either sham operated (normal serum E2 and gonadotropins), ovariectomized (low serum E2 and high serum gonadotropins) or ovariectomized and treated with the GnRH agonist leuprolide acetate (low serum E2 and gonadotropins). Ovariectomy induced a 2.2-fold increase in Evan's blue dye extravasation into the brain. The expression and localization of the cytoplasmic membrane-associated tight junction protein zona occludens 1 (ZO-1) in microvessels was not altered among groups indicating that the increased paracellular permeability was not due to changes in this tight junction protein. However, ovariectomy induced a redistribution of the gap junction protein connexin-43 (Cx43) such that immunoreactivity relocalized from along the extracellular microvascular endothelium to become associated with endothelial cells. An increase in Cx43 expression in the mouse brain following ovariectomy was suppressed in ovariectomized animals treated with leuprolide acetate, indicating that serum gonadotropins rather than sex steroids were modulating Cx43 expression. These results suggest that elevated serum gonadotropins following reproductive senescence may be one possible cause of the loss of selective permeability of the BBB at this time. Furthermore, these findings implicate Cx43 in mediating changes in BBB permeability, and serum gonadotropins in the cerebropathophysiology of age-related neurodegenerative diseases such as stroke and Alzheimer's disease.
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PMID:Reproductive hormones regulate the selective permeability of the blood-brain barrier. 1838 Dec 7

Although the function of astrocytic gap junctions under ischemia is still under debate, increased expression of connexin 43 (Cx43) has been observed in ischemic brain lesions, suggesting that astrocytic gap junctions could provide neuronal protection against ischemic insult. Moreover, different connexin subtypes may play different roles in pathological conditions. We used immunohistochemical analysis to investigate alterations in the expression of connexin subtypes in human stroke brains. Seven samples, sectioned after brain embolic stroke, were used for the analysis. Data, evaluated semiquantitatively by computer-assisted densitometry, was compared between the intact hemisphere and ischemic lesions. The results showed that the coexpression of Cx32 and Cx45 with neuronal markers was significantly increased in ischemic lesions. Cx43 expression was significantly increased in the colocalization with astrocytes and relatively increased in the colocalization with neuronal marker in ischemic lesions. Therefore, Cx32, Cx43, and Cx45 may respond differently to ischemic insult in terms of neuroprotection.
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PMID:Ischemia alters the expression of connexins in the aged human brain. 1979 23

Brain damage resulting from cerebral ischemia remains a significant problem at all stages of life. In adults, ischemic stroke is the third leading cause of death and the leading cause of disability in the developed world. In term newborns, moderate to severe brain damage after hypoxia-ischemia (HI) occurs in 1-3 per 1000 live births. One of the most striking features of HI injury is that after initial recovery of cellular oxidative metabolism, there is a delayed, 'secondary' mitochondrial failure that spreads over time from the most severely damaged areas outwards, into previously undamaged regions. This secondary failure is accompanied by transient seizure activity and cytotoxic edema. The specific mechanisms of this spread are poorly understood, but it is at least partly associated with spreading waves of depression that can trigger cell death in neighboring uninjured tissues. The waves are propagated through cell-cell communication via gap junction channels (the so called "bystander effect"). It has recently been proposed that unopposed connexin hemichannels (connexons) also play a significant role by mediating release of paracrine molecules that in turn propagate cell death messages by releasing intracellular mediators such as ATP, NAD(+), or glutamate or by abnormally prolonged opening to allow cell edema. There is increasing evidence that connexin hemichannels contribute to injury after many neural insults and that it is possible to significantly reduce the spread of damage after injury by suppressing the induction or activity of the connexin proteins that form hemichannels.
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PMID:A key role for connexin hemichannels in spreading ischemic brain injury. 2317 Jul 95

Atrial fibrillation (AF) is the most common cardiac arrhythmia and carries a significant risk of stroke and heart failure. The molecular etiologies of AF are poorly understood, leaving patients with limited therapeutic options. AF has been recognized as an inherited disease in almost 30% of patient cases. However, few genetic loci have been identified and the mechanisms linking genetic variants to AF susceptibility remain unclear. By sequencing 193 probands with lone AF, we identified a Q76E variant within the coding sequence of the bone morphogenetic protein (BMP) antagonist gremlin-2 (GREM2) that increases its inhibitory activity. Functional modeling in zebrafish revealed that, through regulation of BMP signaling, GREM2 is required for cardiac laterality and atrial differentiation during embryonic development. GREM2 overactivity results in slower cardiac contraction rates in zebrafish, and induction of previously identified AF candidate genes encoding connexin-40, sarcolipin and atrial natriuretic peptide in differentiated mouse embryonic stem cells. By live heart imaging in zebrafish overexpressing wild-type or variant GREM2, we found abnormal contraction velocity specifically in atrial cardiomyocytes. These results implicate, for the first time, regulators of BMP signaling in human AF, providing mechanistic insights into the pathogenesis of the disease and identifying potential new therapeutic targets.
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PMID:Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm. 2322 79

Alterations in Connexin43 (Cx43) expression levels have been shown to play a role in inflammatory processes including skin wounding and neuroinflammation. Cx43 protein levels increase following a skin wound and can inhibit wound healing. Increased Cx43 has been observed following stroke, epilepsy, ischemia, optic nerve damage, and spinal cord injury with gap junctional communication and hemichannel opening leading to increased secondary damage via the inflammatory response. Connexin43 modulation has been identified as a potential target for protection and repair in neuroinflammation and skin wound repair. This review describes the use of a Cx43 specific antisense oligonucleotide (Cx43 AsODN) and peptide mimetics of the connexin extracellular loop domain to modulate Cx43 expression and/or function in inflammatory disorders of the skin and central nervous system. An overview of the role of connexin43 in inflammatory conditions, how antisense and peptide have allowed us to elucidate the role of Cx43 in these diseases, create models of diseases to test interventions and their potential for use clinically or in current clinical trials is presented. Antisense oligonucleotides are applied topically and have been used to improve wound healing following skin injury. They have also been used to develop ex vivo models of neuroinflammatory diseases that will allow testing of intervention strategies. The connexin mimetic peptides have shown potential in a number of neuroinflammatory disorders in ex vivo models as well as in vivo when delivered directly to the injury site or when delivered systemically.
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PMID:The use of connexin-based therapeutic approaches to target inflammatory diseases. 2402 57

Rather being an inert barrier between vessel lumen and surrounding tissues, vascular endothelium plays a key role in the maintenance of cardiovascular homeostasis. The de-endothelialization of blood vessels is regarded as the early event that results in the onset of severe vascular disorders, including atherosclerosis, acute myocardial infarction, brain stroke, and aortic aneurysm. Restoration of the endothelial lining may be accomplished by the activation of neighbouring endothelial cells (ECs) freed by contact inhibition and by circulating endothelial progenitor cells (EPCs). Intracellular Ca(2+) signalling is essential to promote wound healing: however, the molecular underpinnings of the Ca(2+) response to injury are yet to be fully elucidated. Similarly, the components of the Ca(2+) toolkit that drive EPC incorporation into denuded vessels are far from being fully elucidated. The present review will survey the current knowledge on the role of Ca(2+) signalling in endothelial repair and in EPC activation. We propose that endothelial regeneration might be boosted by intraluminal release of specific Ca(2+) channel agonists or by gene transfer strategies aiming to enhance the expression of the most suitable Ca(2+) channels at the wound site. In this view, connexin (Cx) channels/hemichannels and store-operated Ca(2+) entry (SOCE) stand amid the most proper routes to therapeutically induce the regrowth of denuded vessels. Cx stimulation might trigger the proliferative and migratory behaviour of ECs facing the lesion site, whereas activation of SOCE is likely to favour EPC homing to the wounded vessel.
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PMID:Endothelial remodelling and intracellular calcium machinery. 2423 52


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