Implication of connexins 40 and 43 in functional coupling between mouse cardiac fibroblasts in primary culture

Louault, Claire; Benamer, Najate; Faivré, Jean-François; Potreau, Daniel; Bescond, Jocelyn

doi:10.1016/j.bbamem.2008.04.005

Cited by 34 publications

(24 citation statements)

References 43 publications

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“…Moreover, TNF-α and connexin-43, which promote anti-apoptosis 39 and cell migration 45, 52 , was significantly up-regulated in the supernatant of cardiac stem cells and correlated with the significantly increased gene expression of TNF-α in hCM- and iCM-treated heart tissue. SDF1α was also significantly up-regulated in the iCM supernatant compared to the iPSC.…”

Section: Discussionmentioning

confidence: 92%

Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

Tachibana

Santoso

Mahmoudi

et al. 2017

Circulation Research

139

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Rationale Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction (LVEF). However, the mechanism underlying the functional benefit is unclear. Objective To evaluate whether the transplantation of cardiac lineage differentiated derivatives enhance myocardial viability and restore LVEF more effectively than undifferentiated pluripotent stem cells after a myocardial injury (MI). Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine MI model. Methods and Results Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intra-myocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14) and (5) PBS control (n=10). LVEF and myocardial viability, measured by cardiac-MRI and manganese-enhanced MRI (MEMRI), respectively, was significantly improved in hCM- and iCM-treated mice compared to pluripotent stem cell- or control-treated mice. Bioluminescence imaging (BLI) revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant up-regulation of the pro-migratory, pro-angiogenic, and anti-apoptotic targets in groups treated with cardiac lineage cells compared to pluripotent stem cell and control groups. Conclusions This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium more effectively than undifferentiated stem cells through their differential paracrine effects.

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Section: Discussionmentioning

confidence: 92%

Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

Tachibana

Santoso

Mahmoudi

et al. 2017

Circulation Research

139

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“…S7). PGF 2␣ , the dominant product of COX-2 in fibroblasts, can itself further up-regulate fibroblast COX-2-dependent PGF 2␣ formation in a feed-forward manner (56) and thereby promote fibrosis (57) and, potentially, connexin43 heterogenity (58). Interestingly, while infusion of E and I prostanoids protect against experimentally induced arrhythmias, PGF 2␣ promotes arrhythmogenesis in vitro (52) and deletion of F-prostanoid receptor protects against inflammatory tachycardia in vivo (59).…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Wang

Patel

Ricciotti

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

110

105

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Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the ␣-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.arrhythmia ͉ heart failure ͉ knockout ͉ NSAIDs ͉ fibrosis R andomized, placebo-controlled trials indicate that nonsteroidal antinflammatory drugs (NSAIDs) specific for inhibition of cyclooxygense (COX)-2 confer an increased risk of myocardial infarction and stroke (1-5), effects explicable by suppression of COX-2-derived products, such as prostacyclin (PGI 2 ) and prostaglandia E 2 (PGE 2 ) (6). While, the clinical spectrum of hazard is dominated by a predisposition to thrombosis, an additional feature has been congestive heart failure (1-4). NSAIDs may variably increase blood pressure (7): studies in rodents (8, 9) and a meta-analysis of clinical studies (10) suggest that this reflects inhibition of COX-2 and the specificity with which this is attained (11). Elevation of blood pressure by manipulation of the prostaglandin pathway is conditioned by genetic background in rodents (12). However, given this caveat, deletion or inhibition of COX-2 (8, 13) and deletion of the E prostanoid (EP)-2 receptor (14, 15) or the I-prostanoid receptor (IP) (16) for the COX-2 products, PGE 2 and PGI 2 respectively, may each result in hypertension. Indeed, deletion of the IP in these mice also results in cardiac hypertrophy and fibrosis, effects ameliorated by coincident deletion of the receptor for thromboxane A 2 , the TP, a maneuver that does not, alone, affect blood pressure (16). By contrast, inhibition or deletion of COX-1 attenuates the hypertensive response to infusion of angiotensin II (8) or treatment with a COX-2 inhibitor (13). Although placebo-controlled trials provide unequivocal evidence that COX-2-specific NSAIDs confer a cardiovascular hazard, the number of events within each trial are insufficient to permit analysis of covariates. Thus, it is unknown whether congestive heart failure on NSAIDs results solely from or is exacerbated by hypertension.Although suppression of COX-2-derived prostanoids is sufficient to explain the cardiovascular hazard conferred by purposedesigned and older NSAIDs specific for inhibition of COX-2 (17), there has been interest in the possibility that some or all of these effects might reflect ''off target'' effects. One such example was an overview-trial analysis interpreted to suggest that arrhythmia, cardiac arrest, ...

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“…In the heart where coupling of the cells is essential for a regular impulse generation, propagation and contraction, three main connexins have been detected: Cx40, Cx43 and Cx45 (see Table 1 for connexin properties). All these three occur in cardiomyocytes (Davis et al 1995) as well as in cardiac fibroblasts (Doble and Kardami 1995;Camelliti et al 2004;Louault et al 2008). Besides these three connexins, two more connexins are found in cardiac vasculature: Cx37 which is present in endothelial cells and Cx32 which is located in smooth muscles cells (Christ et al 1996;Nielsen and Kumar 2003).…”

Section: Introductionmentioning

confidence: 95%

Adrenergic control of cardiac gap junction function and expression

Salameh

Dhein²

2011

Naunyn-Schmied Arch Pharmacol

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Electrical intercellular communication in the heart allows the propagation of an action potential from cell to cell. This is realized by low-ohmic cell-to-cell channels, the gap junction channels, which are dodecameric proteins consisting of two hexameric hemichannels. Each of the neighbouring cell provides one hemichannel, which consists of six connexins. In the heart, the connexin isoforms Cx43, Cx40 and Cx45 are present with Cx43 being the most abundant isoform. This intercellular communication is regulated acutely by control of the gap junction conductance and chronically by control of the connexin expression. The short half-life time of Cx43 indicates the permanent adaptation of cell communication to the actual requirements. β-Adrenoceptor stimulation enhances Cx40- but reduces Cx45-conductance, while Cx43 channels in most species do not seem to be acutely affected by β-adrenoceptor signalling. In contrast, chronic exposure to β-adrenergic stimulants activates protein kinase A and the mitogenic-activated protein kinase cascade (including protein 38 (p38), mitogenic-activated protein kinase kinase 1, extracellular signal-regulated kinase (ERK)1/2 and c-JUN NH(2) terminal kinase (JNK)), the calcineurin pathway, translocation of activator protein 1 (AP1), CRE-binding protein and nuclear factor of activated T cells, finally leading to enhanced Cx43-mRNA and Cx43-protein expression together with Cx43 phosphorylation, but does not affect Cx40. α-Adrenoceptors also play a role in controlling cardiac intercellular communication: α-adrenergic stimulation acutely uncouples the cells, while a chronic stimulation enhances Cx43 expression via protein kinase C, p38, ERK1/2, JNK, c-fos and AP1, but does not alter Cx40 expression. While general cardiac protein synthesis, e.g. of β-actin, is controlled via α(1A)-adrenoceptors, Cx43 expression is regulated via α(1D)-adrenoceptors. However, α-adrenoceptor density in the heart varies among species, with high abundance in rat heart and low in human heart. Acute α-adrenergic stimulation, e.g. during ischemia, can lead to uncoupling and facilitates re-entrant arrhythmia. Chronic adrenergic upregulation of Cx43 expression seems to be involved in cardiac hypertrophy. In maladaptive hypertrophy, the enhanced Cx43 is increasingly incorporated in the lateral membrane of the cells rather at the cell poles, which may mean a gap junction disarray. This could-together with a mismatch in cell size and coupling-contribute to arrhythmogenesis. Thus, cardiac adrenoceptors are directly involved in the control of intercellular electrical communication and thus probably are a critical factor in the maintenance of regular cell-to-cell conduction and of the cardiac electrical networking. They probably are involved in the formation of an arrhythmogenic substrate in certain heart diseases.

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Implication of connexins 40 and 43 in functional coupling between mouse cardiac fibroblasts in primary culture

Cited by 34 publications

References 43 publications

Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Adrenergic control of cardiac gap junction function and expression

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