Autocrine Regulation of Myocyte Cx43 Expression by VEGF

Pimentel, Rhea; Yamada, Kathryn A.; Kléber, André G.; Saffitz, Jeffrey E.

doi:10.1161/01.res.0000014823.75393.4d

Cited by 111 publications

(106 citation statements)

References 42 publications

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“…32,34 Our results suggest that heterocellular endothelial-CM junctions may exist between CMs and ECs, which has not been reported for adult cardiac tissue. 24 Interestingly, a recent study demonstrated that VEGF enhanced Cx43 expression in myocytes, 37 suggesting that a VEGF-dependent mechanism for signaling between ECs and myocytes may also play a role in our system. We observed no differences in either apoptosis or Cx43 staining between VEGF antibodycontaining cultures and controls; further experiments will be necessary to determine whether other cytokines or growth factors mediate these effects.…”

Section: Narmoneva Et Al Endothelial Cells and Cardiomyocytes 965mentioning

confidence: 92%

Endothelial Cells Promote Cardiac Myocyte Survival and Spatial Reorganization

et al. 2004

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Section: Narmoneva Et Al Endothelial Cells and Cardiomyocytes 965mentioning

confidence: 92%

Endothelial Cells Promote Cardiac Myocyte Survival and Spatial Reorganization

et al. 2004

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“…Included in this list were TGF-β-1-induced transcript 4, TGF-β-induced-microtubuleassociated protein 4, dermatopontin, matrix metalloproteinase 3, serine protease 11 (IGF binding), gap junction membrane channel protein alpha 1, zinc-finger homeobox 1a, and others (Verrecchia et al, 2001;Pimentel et al, 2002;Chambers et al, 2003). Although tumor cells and surrounding stroma often produce abundant TGF-β ligands (Reiss, 1999), the altered expression of these TGF-β targets lead us to hypothesize that the TGF-β pathway might be downregulated in ErbB2/Neu-induced tumors.…”

Section: The Molecular Profile Of Erbb2/neu Tumors Suggests That Thesmentioning

confidence: 99%

Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-β signaling in ErbB2/Neu-induced tumors from transgenic mice

et al. 2005

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Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-β target genes was altered, suggesting that the TGF-β signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-β-Receptor-I/ALK5 and immunohistochemistry for TGF-β-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-β signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of ActivinReceptor-IB/ALK4, suggesting that although Smad-dependent TGF-β signaling is absent in ErbB2/ Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-β pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-β-Receptor-I/ALK5.

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“…A previous study found that VEGF upregulated expression of Cx43 and that inhibition of VEGF downregulated Cx43 expression 41. Another study revealed that in cardiac organoids, or engineered simplified heart chambers, VEGF upregulated Cx43 and enhanced cardiac function 42.…”

Section: Discussionmentioning

confidence: 99%

Disruption of VEGF Mediated Flk‐1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino‐1

Thirunavukkarasu

Selvaraju

Joshi

et al. 2018

JAHA

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BackgroundThe present study demonstrates that the ubiquitin E3 ligase, Pellino‐1 (Peli1), is an important angiogenic molecule under the control of vascular endothelial growth factor (VEGF) receptor 2/Flk‐1. We have previously reported increased survivability of ischemic skin flap tissue by adenovirus carrying Peli1 (Ad‐Peli1) gene therapy in Flk‐1+/− mice.Methods and ResultsTwo separate experimental groups of mice were subjected to myocardial infarction (MI) followed by the immediate intramyocardial injection of adenovirus carrying LacZ (Ad‐LacZ) (1×109 pfu) or Ad‐Peli1 (1×109 pfu). Heart tissues were collected for analyses. Compared with wild‐type (WTMI) mice, analysis revealed decreased expressions of Peli1, phosphorylated (p‐)Flk‐1, p‐Akt, p‐eNOS, p‐MK2, p‐IκBα, and NF‐κB and decreased vessel densities in Flk‐1+/− mice subjected to MI (Flk‐1+/− MI). Mice (CD1) treated with Ad‐Peli1 after the induction of MI showed increased β‐catenin translocation to the nucleus, connexin 43 expression, and phosphorylation of Akt, eNOS, MK2, and IκBα, that was followed by increased vessel densities compared with the Ad‐LacZ–treated group. Echocardiography conducted 30 days after surgery showed decreased function in the Flk1+/− MI group compared with WTMI, which was restored by Ad‐Peli1 gene therapy. In addition, therapy with Ad‐Peli1 stimulated angiogenic and arteriogenic responses in both CD1 and Flk‐1+/− mice following MI. Ad‐Peli1 treatment attenuated cardiac fibrosis in Flk‐1+/− MI mice. Similar positive results were observed in CD1 mice subjected to MI after Ad‐Peli1 therapy.ConclusionOur results show for the first time that Peli1 plays a unique role in salvaging impaired collateral blood vessel formation, diminishes fibrosis, and improves myocardial function, thereby offering clinical potential for therapies in humans to mend a damaged heart following MI.

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Autocrine Regulation of Myocyte Cx43 Expression by VEGF

Cited by 111 publications

References 42 publications

Endothelial Cells Promote Cardiac Myocyte Survival and Spatial Reorganization

Endothelial Cells Promote Cardiac Myocyte Survival and Spatial Reorganization

Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-β signaling in ErbB2/Neu-induced tumors from transgenic mice

Disruption of VEGF Mediated Flk‐1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino‐1

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