Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF

Yoshioka, Jun; Prince, Robin N.; Huang, Hayden; Perkins, Scott B.; Cruz, Francisco U.; MacGillivray, Catherine; Lauffenburger, Douglas A.; Lee, Richard T.

doi:10.1073/pnas.0501198102

Cited by 57 publications

(47 citation statements)

References 32 publications

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“…Studies showed that local overexpression of HB-EGF elevated the levels of left ventricular hypertrophy, apoptosis, and fibrosis following myocardial infarction (20). Moreover, the local disruption in gap junctions might be a part of the hypertrophic response induced by HB-EGF (27). So the prevention of cardiac remodeling such as cardiac hypertrophy, fibrosis, and gap junction remodeling by Rb1 administration appeared to be correlated with decreasing expression of HB-EGF in cTnT R141W transgenic mice.…”

Section: Discussionmentioning

confidence: 94%

Ginsenoside-Rb1 Attenuates Dilated Cardiomyopathy in cTnTR141W Transgenic Mouse

et al. 2010

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Abstract. Familial dilated cardiomyopathy (FDCM) is caused by defective genes and specific medicines are not currently available to treat this. Ginsenoside-Rb1 provides cardioprotection in the experimental models of myocardial ischemia-reperfusion injury. Here we investigate Rb1's effect on DCM in cTnT R141W transgenic mouse. The transgene-positive mice aged 2 months were randomized into the model group and Rb1 [70 mg/(kg·day)] group; transgene-negative mice were used as a control. After 4-month treatment, cardiac function was assessed by echocardiography; cardiac tissues were prepared for histology and electron microscopy. Expression levels of molecular markers of cardiac hypertrophy, fibrosis, and intercalated disc proteins were detected by RT-PCR. Rb1 significantly decreased mortality, chamber dilation, and contractile dysfunction in cTnT R141W mice. Rb1 attenuated cardiac hypertrophy, interstitial fibrosis, ultrastructural degeneration, and intercalated disc remodeling in DCM hearts. Western blotting showed that Rb1 significantly decreased heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression and signal transduction and activators of transcription 3 (STAT3) activation, which were gradually increased in DCM hearts. Our results showed that Rb1 clearly alleviated cardiac dysfunction and remodeling in the cTnT R141W transgenic mouse, indicating its potential utility in the treatment of FDCM.

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Section: Discussionmentioning

confidence: 94%

Ginsenoside-Rb1 Attenuates Dilated Cardiomyopathy in cTnTR141W Transgenic Mouse

et al. 2010

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“…Wounding sheets of corneal epithelial cells causes release of heparin-binding EGF-like growth factor and amphiregulin (19,20,22,32). Both of these ligands bind strongly to negatively charged glycans in the extracellular matrix and the cell surface (56)(57)(58). This limits their diffusion and provides an explanation why the receptor is activated only very locally.…”

Section: Discussionmentioning

confidence: 99%

Dual modes of motility at the leading edge of migrating epithelial cell sheets

Klarlund

2012

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

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Purse-string healing is driven by contraction of actin/myosin cables that span cells at wound edges, and it is the predominant mode of closing small round wounds in embryonic and some adult epithelia. Wounds can also heal by cell crawling, and my colleagues and I have shown previously that the presence of unconstrained, straight edges in sheets of epithelial cells is a sufficient signal to induce healing by crawling. Here, it is reported that the presence of highly concave edges, which are free or physically constrained by an inert material (agarose), is sufficient to induce formation of purse strings. It was determined that neither of the two types of healing required cell damage or other potential stimuli by using the particularly gentle procedure of introducing gaps by digesting agarose blocks imbedded in the cell sheets. Movement by crawling depends on signaling by the EGF receptor (EGFR); however, this was not required for purse-string contraction. A migrating epithelial cell sheet usually produces finger-like projections of crawling cells. The cells between fingers contain continuous actin cables, which were also determined to contain myosin IIA and exhibit additional characteristics of purse strings. When crawling was blocked by inhibition of EGFR signaling, the concave regions continued to move, suggesting that both mechanisms contribute to propel the sheets forward. Wounding epithelial cell sheets causes activation of the EGFR, which triggers movement by crawling. The EGFR was found to be activated only at straight and convex edges, which explains how both types of movement can coexist at leading epithelial edges.

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“…34 Recently, heparin-binding epidermal growth factor has been shown to lead to cell hypertrophy and reduced Cx43 expression in cultured cardiomyocytes in a local autocrine/paracrine manner. 35 In contrast, angiotensin II, transforming growth factor-(TGF-) and VEGF are reported to be involved in pulsatile stretch-induced upregulation of Cx43 in cell culture. 29,31,32 Nevertheless, further experimental studies are required to elucidate the precise molecular mechanisms underlying dephosphorylation and translocation of Cx43 in gap junction remodeling associated with cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Internalization and Dephosphorylation of Connexin43 in Hypertrophied Right Ventricles of Rats With Pulmonary Hypertension

Sasano

Honjo

Takagishi

et al. 2007

Circ J

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ap junctions are specialized membrane regions consisting of groups of channels that directly connect the cytoplasmic components of adjacent cells and enable intercellular communication with respect to the exchange of ions and small (<1 kDa) molecules. 1 Gap junctions are composed of transmembrane proteins that belong to the connexin family. The principal gap junctional protein expressed in ventricles of the mammalian heart is connexin43 (Cx43), although connexin40, connexin45 and connexin 30.2 (and its human ortholog, connexin31.9) are also expressed in other regions of the heart. [2][3][4] Remodeling of gap junction in the heart is an important feature of the structural substrates for conduction disturbance and arrhythmogenesis under various pathological conditions including myocardial ischemia, infarction and hypertrophy. [2][3][4][5][6][7][8] In our previous immunohistochemical studies on rats with pressure overload-induced ventricular hypertrophy, we have shown that the cellular distribution of gap junctions are altered; in normal ventricles Cx43 gap junctions are largely confined to the intercalated disks at the cell termini, but in hypertrophied ventricles, Cx43 gap junctions are displaced from the intercalated disks and widely distributed. 9,10 Cx43 is a phosphoprotein, and the phosphorylation/dephosphorylation of Cx43 plays important roles in the regulation of protein turnover dynamics (trafficking, plaque assembly, internalization and degradation) as well as channels gating properties. 1,[11][12][13][14] In the hearts subjected to acute ischemia, [15][16][17] and in non-ischemic heart failure, 18 as well as in dilated cardiomyopathy, 19 dephosphorylation of Cx43 was shown to play an important role in its disorganization and electrical uncoupling of ventricular cells under the pathological conditions. It is well known that ventricular hypertrophy is associated with the activation or inhibition of various types of protein kinases and/or phosphatases. We, therefore, hypothesized that phosphorylation/dephosphorylation of Cx43 could also be involved in the disorganization of Cx43 gap junctions in the pressure-overload ventricular hypertrophy.In the present study, we have investigated the expression and distribution of Cx43 and its phosphorylation state in hypertrophied ventricles of rats with monocrotaline (MCT)-induced pulmonary hypertension by immunoconfocal and electron microscopy, as well as immunoblotting using isoform-specific antibodies. Background Altered expression and distribution of gap junctions might provide substrates for abnormal conduction and arrhythmogenesis in the heart, but little is known about the regulation of gap junctions under pathological conditions. The organization and phosphorylation state of connexin43 (Cx43) in ventricular hypertrophy will be investigated. Methods and ResultsRight ventricular (RV) hypertrophy was induced in rats by treatment with monocrotaline. Subcellular Cx43 distribution was assessed by immunoconfocal and electron microscopy. Immunolabeling of Cx43 was conf...

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Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF

Cited by 57 publications

References 32 publications

Ginsenoside-Rb1 Attenuates Dilated Cardiomyopathy in cTnTR141W Transgenic Mouse

Ginsenoside-Rb1 Attenuates Dilated Cardiomyopathy in cTnTR141W Transgenic Mouse

Dual modes of motility at the leading edge of migrating epithelial cell sheets

Internalization and Dephosphorylation of Connexin43 in Hypertrophied Right Ventricles of Rats With Pulmonary Hypertension

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