Cardiac β‐adrenergic receptor activation mediates distinct and cell type‐dependent changes in the expression and distribution of connexin 43

Zhang, Yi; Hou, Meng-Chen; Li, Jingjing; She, Gang; Ren, Yujie; Wu, Wei; Pang, Zheng-Da; Xie, Wenjun; Deng, Xingming; Du, Xiao‐Jun

doi:10.1111/jcmm.15469

Cited by 19 publications

(21 citation statements)

References 54 publications

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“…Protein immunoblotting was performed as previously described 9 , 21 . Protein was extracted from LV tissue by homogenization of tissues with lysis buffer containing phosphatase protease inhibitors.…”

Section: Methodsmentioning

confidence: 99%

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Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice

Wu¹,

Ziemann²,

Huynh³

et al. 2021

Theranostics

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Rationale: Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM). Methods: Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed. Results: In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets. Conclusion: Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.

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Section: Methodsmentioning

confidence: 99%

“…Two independent methods were applied in determination of ROS, as we previously described 21 , 22 . First, O 2- formation was estimated using OCT fresh-frozen LV sections (5 μm) incubated with dihydroethidium (DHE 5 μM, Invitrogen Co.) for 1 h at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice

Wu¹,

Ziemann²,

Huynh³

et al. 2021

Theranostics

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“…Beta-adrenoceptor stimulation has been shown to result in an up-regulation of Cx43 expression (see Table 2, Salameh et al, 2006 [82,83]. The reduced expression and lateral distribution of Cx43 in cardiomyocytes after β-adrenoceptor stimulation was also shown by others which interestingly was associated with the inverse effects in cardiac fibroblasts (Zhang et al, 2020) [84]. Previously, it was shown that cardiac fibroblasts inhibit β-adrenoceptor-dependent Cx43 signaling in cardiomyocytes involving angiotensin II (Salameh et al, 2013) [85].…”

Section: Gap Junction Remodeling In Atrial Fibrillation (Af)mentioning

confidence: 82%

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Dhein

Salameh

2021

Cells

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The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment.

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“…Notably, TGF‐β1 induces an increase of Cx43 that allows the myofibroblasts to couple electrically with the functional tissue‐specific cell type; nonetheless, it might have undesirable consequences. In the cardiac tissue, for instance, where Cx43 is the most abundant isoform of GJs (Zhang et al., 2020), myofibroblasts can cause a substantial TGF‐β1‐dependent depolarization of the cardiomyocytes, as a result of electrotonic cross‐talk that results in a detrimental arrhythmogenic condition (Nagaraju et al., 2019).…”

Section: Discussionmentioning

confidence: 99%

Platelet‐rich plasma affects gap junctional features in myofibroblasts in vitro via vascular endothelial growth factor (VEGF)‐A/VEGF receptor

Sassoli

Garella

Chellini

et al. 2022

Experimental Physiology

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New Findings What is the central question of this study?It is a challenge to discover effective therapies for fibrosis. Increasing evidence supports the antifibrotic potential of platelet‐rich plasma (PRP) as a source of bioactive molecules, such as vascular endothelial growth factor (VEGF)‐A. However, the effects and mechanisms of action of PRP need to be clarified. What is the main finding and its importance?This report clarifies the mechanisms mediating the antifibrotic action of PRP, strengthening the role of VEGF‐A/VEGF receptor, and identifies gap junction currents and connexin 43 as novel targets of this pathway in the fibroblast‐to‐myofibroblast transition induced by the transforming growth factor‐β1. Abstract Despite increasing experimental evidence, the antifibrotic potential of platelet‐rich plasma (PRP) remains controversial, and its mechanisms of action are not fully clarified. This short report extends our previous research on the capability of PRP to prevent the in vitro differentiation of fibroblasts toward myofibroblasts, the key effectors of fibrosis, induced by the profibrotic agent transforming growth factor‐β1 (TGF‐β1). In particular, we focused on the involvement of signalling mediated by vascular endothelial growth factor (VEGF)‐A/VEGF receptor (VEGFR) in the PRP‐induced fibroblast response, highlighting gap junction features. Electrophysiological and morphological analyses revealed that PRP hindered morphofunctional differentiation of both murine NIH/3T3 and human primary adult skin fibroblasts toward myofibroblasts as judged by the analysis of membrane phenomena, α‐smooth muscle actin and vinculin expression and cell morphology. Neutralization of VEGF‐A by blocking antibodies or pharmacological inhibition of VEGFR by KRN633 in TGF‐β1‐treated fibroblasts prevented the PRP‐promoted effects, such as the reduction of voltage‐dependent transjunctional currents in cell pairs and a decreased expression of connexin 43, the typical connexin isoform forming voltage‐dependent connexons. The role of VEGF‐A in inhibiting these events was confirmed by treating TGF‐β1‐stimulated fibroblasts with soluble VEGF‐A. The results obtained when cells were differentiated using KRN633 alone suggest an antagonistic cross‐talk between TGF‐β1 and VEGFR. In conclusion, this study identifies, for the first time, gap junction currents as crucial targets in the VEGF‐A/VEGFR‐mediated antifibrotic pathway and provides new insights into mechanisms behind the action of PRP in preventing differentiation of fibroblasts to myofibroblasts.

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Cardiac β‐adrenergic receptor activation mediates distinct and cell type‐dependent changes in the expression and distribution of connexin 43

Cited by 19 publications

References 54 publications

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice

Activation of Hippo signaling pathway mediates mitochondria dysfunction and dilated cardiomyopathy in mice

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

Platelet‐rich plasma affects gap junctional features in myofibroblasts in vitro via vascular endothelial growth factor (VEGF)‐A/VEGF receptor

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