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B-Receptor Signaling in Cardiomyopathy

ABSTRACT: We hope to determine the importance of different genes (including B receptors) in anthracycline-induced cardiomyopathy. This has important benefits to patients exposed to anthracyclines, as this could help determine whether certain individuals have increased susceptibility to cardiac injury.

DISEASE(S): Gastrointestinal Stromal Tumor (gist),Carcinoma,Myeloproliferative Disorders,Carcinoma, Transitional Cell,Mesothelioma,Thymus Neoplasms,Urinary Bladder Neoplasms,Eye Neoplasms,Brain Neoplasms,Carcinoma, Renal Cell,Cardiomyopathies,Head And Neck Cancers,Stomach Neoplasms,Gall Bladder Cancer,Multiple Myeloma,Thymus Cancer,Transitional Cell Carcinoma Of Bladder,Anemia,Preleukemia,Soft Tissue Sarcoma,Pancreatic Cancer,Eye Cancer,Myelodysplastic Syndromes (mds),Bone Marrow Transplant Failure,Gastrooesophageal Cancer,Esophageal Cancer,Endocrine Cancer,Anal Cancer,Testicular Neoplasms,Kidney (renal Cell) Cancer,Carcinomas,Neuroendocrine Tumors,Lung Cancer,Leukemia,Hodgkin Disease,Testicular Cancer,Skin Cancer,Hepatobiliary Neoplasm,Cholangiocarcinoma,Myelodysplastic Syndromes,Sarcoma,Gynecologic Cancers,Breast Cancer,Anus Neoplasms,Bone Neoplasms,Bone Cancer,Gastric (stomach) Cancer,Cholangiocarcinoma Of The Extrahepatic Bile Duct,Thyroid Cancer,Cancer Of Brain And Nervous System,Gallbladder Neoplasms,Endocrine Gland Neoplasms,Lymphoma, Non-hodgkin,Carcinoma Of The Large Intestine,Prostate Cancer,Amyloidosis,Gastrointestinal Stromal Tumors

PROVIDER: 2090060 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a M-bM-^@M-^\rapidM-bM-^@M-^] non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear. Methods and Results: Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in E2-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of E2 to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury. Conclusions: Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents. Transgenic disrupting peptide mice (DPM) express the Estrogen Receptor (ER) alpha amino acids 176-253 peptide under CMV promoter control. This peptide blocks interactions between ER and striatin, which inhibits rapid non-genomic signaling by ER to cellular kinases. Female WT and DPM mice (4 mice per sample) were overiectomized, and 1 week later aortas were harvested and treated + 10 nM beta-estradiol (E2) or + EtOH vehicle (Veh) for 4 hrs ex vivo. Total RNA was collected, reverse transcribed to cDNA and used to probe Affymetrix mouse 430.A 2.0 arrays.

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B-Receptor Signaling in Cardiomyopathy

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