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Jamie Seymour - One of the best experts on this subject based on the ideXlab platform.
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rapid short term and gradual permanent Cardiotoxic effects of vertebrate toxins from chironex fleckeri australian box jellyfish venom
Toxicon, 2014Co-Authors: Stephanie Chaousis, Michael J Smout, David Wilson, Alex Loukas, Jason Mulvenna, Jamie SeymourAbstract:The vertebrate Cardiotoxic components of the venom produced by the Australian box jellyfish, Chironex fleckeri, have not previously been isolated. We have uncovered for the first time, three distinct cytotoxic crude fractions from within the vertebrate Cardiotoxic peak of C. fleckeri venom by monitoring viability of human muscle cells with an impedance based assay (ACEA xCELLigence system) measuring cell detachment as cytotoxicity which was correlated with a reduction in cell metabolism using a cell proliferation (MTS) assay. When the effects of the venom components on human cardiomyocytes and human skeletal muscle cells were compared, two fractions were found to specifically affect cardiomyocytes with distinct temporal profiles (labelled Crude Toxic Fractions (CTF), α and β). A third fraction (CTF-γ) was toxic to both muscle cell types and therefore not cardio specific. The vertebrate, cardio specific CTF-α and CTF-β, presented distinct activities; CTF-α caused rapid but short term cell detachment and reduction in cell metabolism with enhanced activity at lower concentrations than CTF-β. This activity was not permanent, with cell reattachment and subsequent increased metabolism of heart muscle cells observed when exposed to all but the highest concentrations of CTF-α tested. The cytotoxic effect of CTF-β took twice as long to act on the cells compared to CTF-α, however, the activity was permanent. Furthermore, we showed that the two fractions combined have a synergistic effect causing a much stronger and faster cell detachment (death) when combined than the sum of the individual effects of each toxin. These data presented here improves the current understanding of the toxic mechanisms of the Australian box jellyfish, C. fleckeri, and provides a basis for in vivo research of these newly isolated toxic fractions.
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Cardiotoxic effects of venom fractions from the australian box jellyfish chironex fleckeri on human myocardiocytes
Toxicon, 2012Co-Authors: Silvia Saggiomo, Jamie SeymourAbstract:An investigation into the Cardiotoxic effects in human cardiomyocytes of different fractions (as produced from an FPLC) of the venom from Chironex fleckeri showed that whole venom caused cardiac cell death in minutes, measured as cell detachment using xCELLigence technology. However, only one fraction of the venom was responsible for this effect. When all extracted venoms were recombined a similar result was seen for the toxic fraction, however these effects were slower than unfractionated venom alone even though the concentrations were similar. The difference in the results between fractioned and unfractionated venom may have been caused by compounds remaining in the FPLC column, which may interact with the toxic fraction to cause rapid cell detachment or death.
Steven E. Lipshultz - One of the best experts on this subject based on the ideXlab platform.
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Chemotherapy-induced Cardiotoxicity in children
Expert Opinion on Drug Metabolism & Toxicology, 2017Co-Authors: Neha Bansal, Shahnawaz M. Amdani, Emma R. Lipshultz, Steven E. LipshultzAbstract:ABSTRACTIntroduction: With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of Cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents.Areas covered: This review covers the various Cardiotoxic chemotherapeutic agents, the pathophysiology of Cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline Cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer t...
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Cardiovascular Effects of Cancer Therapy
Pediatric Oncology, 2015Co-Authors: David A. Briston, Thomas R. Cochran, Peter J. Sambatakos, Stefanie R. Brown, Steven E. LipshultzAbstract:During the past 40 years, advances in cancer treatment have drastically improved survival rates for children with cancer. Of the 325,000 childhood cancer survivors in the United States, 24 % have survived greater than 30 years from diagnosis. This growing population of survivors brings the wide array of potential late effects of cancer therapy to light. The developing cardiovascular system is particularly vulnerable to Cardiotoxic cancer therapies such as anthracyclines and radiation. These treatment modalities have been found to result in chronic, progressive cardiac dysfunction occurring months to decades after treatment.
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Anthracycline-Induced Cardiotoxicity: A Review of Pathophysiology, Diagnosis, and Treatment
Current Treatment Options in Cardiovascular Medicine, 2014Co-Authors: Vivian I. Franco, Steven E. LipshultzAbstract:Anthracyclines have been widely used in children and adults to treat hematologic malignancies, soft-tissue sarcomas, and solid tumors. However, anthracyclines come with both short- and long-term Cardiotoxic effects, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and heart failure that may result in cardiac transplantation or death. Here, we review the progress made over the past two decades in understanding the molecular and genetic basis of anthracycline-induced Cardiotoxicity; detecting and monitoring myocardial dysfunction; using adjunct cardioprotectant therapies, such as dexrazoxane; and improving cardioprotection with agents such as liposomal and pegylated doxorubicin. Despite this increased understanding, preventing drug-induced Cardiotoxicity while maintaining oncologic efficacy to achieve the highest quality of life over a lifespan remain cornerstones of successful anthracycline chemotherapy during childhood.
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cardiovascular status of childhood cancer survivors exposed and unexposed to Cardiotoxic therapy
Journal of Clinical Oncology, 2012Co-Authors: Steven E. Lipshultz, David C Landy, Gabriela Lopezmitnik, Stuart R Lipsitz, Andrea S Hinkle, Louis S Constine, Carol A French, Amy M Rovitelli, Cindy Proukou, Jacob M AdamsAbstract:Purpose To determine whether cardiovascular abnormalities in childhood cancer survivors are restricted to patients exposed to Cardiotoxic anthracyclines and cardiac irradiation and how risk factors for atherosclerotic disease and systemic inflammation contribute to global cardiovascular status. Methods We assessed echocardiographic characteristics and atherosclerotic disease risk in 201 survivors of childhood cancer with and without exposure to Cardiotoxic treatments at a median of 11 years after diagnosis (range, 3 to 32 years) and in 76 sibling controls. Results The 156 exposed survivors had below normal left ventricular (LV) mass, wall thickness, contractility, and fractional shortening and above normal LV afterload. The 45 unexposed survivors also had below normal LV mass overall, and females had below normal LV wall thickness. Exposed and unexposed survivors, compared with siblings, had higher levels of N-terminal pro-brain natriuretic peptide (81.7 and 69.0 pg/mL, respectively, v 39.4 pg/mL), higher mean fasting serum levels of non– high-density lipoprotein cholesterol (126.5 and 121.1 mg/dL, respectively, v 109.8 mg/dL), higher insulin levels (10.4 and 10.5 U/mL, respectively, v 8.2 U/mL), and higher levels of high-sensitivity C-reactive protein (2.7 and 3.1 mg/L, respectively, v 0.9 mg/L; P .001 for all comparisons). Age-adjusted, predicted-to-ideal 30-year risk of myocardial infarction, stroke, or coronary death was also higher for exposed and unexposed survivors compared with siblings (2.16 and 2.12, respectively, v 1.70; P .01 for both comparisons). Conclusion Childhood cancer survivors not receiving Cardiotoxic treatments nevertheless have cardiovascular abnormalities, systemic inflammation, and an increased risk of atherosclerotic disease. Survivorship guidelines should address cardiovascular concerns, including the risk of atherosclerotic disease and systemic inflammation, in exposed and unexposed survivors. J Clin Oncol 30:1050-1057. © 2012 by American Society of Clinical Oncology
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female sex and higher drug dose as risk factors for late Cardiotoxic effects of doxorubicin therapy for childhood cancer
The New England Journal of Medicine, 1995Co-Authors: Steven E. Lipshultz, Suzanne M Mone, Allen M Goorin, Stephen E Sallan, Stephen P Sanders, E J Orav, Richard D Gelber, Steven D ColanAbstract:Background Late Cardiotoxic effects of doxorubicin are increasingly a problem for patients who survive childhood cancer. Cardiotoxicity is often progressive, and some patients have disabling symptoms. Our objective was to identify risk factors for late Cardiotoxicity. Methods We examined echocardiograms from 120 children and adults who had received cumulative doses of 244 to 550 mg of doxorubicin per square meter of body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measurements of blood pressure and left ventricular function, contractility (measured as the stress–velocity index), end-diastolic posterior-wall thickness, end-diastolic dimension, mass, and afterload (measured as end-systolic wall stress) were compared with sex-specific values from a cohort of 296 normal subjects. Results All echocardiographic measurements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe ...
Claudia De Lorenzo - One of the best experts on this subject based on the ideXlab platform.
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Cardiotoxic effects of the novel approved anti erbb2 agents and reverse cardioprotective effects of ranolazine
OncoTargets and Therapy, 2018Co-Authors: Claudia De Lorenzo, Rolando Paciello, Gennaro Riccio, Antonio Barbieri, C Coppola, Nicola MaureaAbstract:Pertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody-drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential Cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their Cardiotoxicity.The Cardiotoxic effects were tested in vitro on rat cardiomyoblasts, human fetal cardiomyocytes, adult-like cardiomyocytes, and in vivo on a mouse model.All the treated cardiac cell lines were significantly affected by treatment with the tested drugs. Surprisingly, TDM1 showed stronger inhibitory effects on cardiac cells with respect to trastuzumab and pertuzumab by more significantly reducing the cell viability and by changing the morphology of these cells. TDM1 also affected the beating phenotype of adult-like cardiomyocytes in vitro and reduced fractional shortening and ejection fraction in vivo in a mouse model. We also found that ranolazine attenuated not only the Cardiotoxic side effects of trastuzumab but also those of pertuzumab and TDM1, when used in combinatorial treatments both in vitro and in vivo, as demonstrated by the recovery of fractional shortening and ejection fraction values in mice pretreated with TDM1.We demonstrated that it is possible to predict the eventual Cardiotoxic effects of novel approved anticancer drugs early by using in vitro and in vivo approaches, which can also be useful to screen in advance the cardioprotective agents, so as to avoid the onset of unwanted Cardiotoxic side effects.
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comparison of preclinical Cardiotoxic effects of different erbb2 inhibitors
Breast Cancer Research and Treatment, 2012Co-Authors: Carmine Fedele, Gennaro Riccio, Antonio Barbieri, C Coppola, Nicola Maurea, Maria Monti, Claudio Arra, Carlo G Tocchetti, Giuseppe Dalessio, Claudia De LorenzoAbstract:Two novel human antitumor immunoconjugates, made up of a human anti-ErbB2 scFv, Erbicin, fused with either a human RNase or the Fc region of a human IgG1, are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. The Erbicin-derived immunoagents (EDIA) target an epitope different from that of trastuzumab, the only humanized antibody currently prescribed for treatment of ErbB2-positive breast cancer (BC). As Trastuzumab has shown Cardiotoxic effects, in this study, we evaluated if any side effects were exerted also by EDIA, used as single agents or in combination with anthracyclines. Furthermore, we compared the in vitro and in vivo Cardiotoxic effects of EDIA with those of the other available anti-ErbB2 drugs: Trastuzumab, 2C4 (Pertuzumab), and Lapatinib. In this article, we show that EDIA, in contrast with Trastuzumab, 2C4, and Lapatinib, have no toxic effects on human fetal cardiomyocytes in vitro, and do not induce additive toxicity when combined with doxorubicin. Furthermore, EDIA do not impair cardiac function in vivo in mice, as evaluated by Color Doppler echocardiography, whereas Trastuzumab significantly reduces radial strain (RS) at day 2 and fractional shortening (FS) at day 7 of treatment in a fashion similar to doxorubicin. Also 2C4 and Lapatinib significantly reduce RS after only 2 days of treatment, even though they showed Cardiotoxic effects less pronounced than those of Trastuzumab. These results strongly indicate that RS could become a reliable marker to detect early cardiac dysfunction and that EDIA could fulfill the therapeutic need of patients ineligible to Trastuzumab treatment because of cardiac dysfunction.
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Cardiotoxic effects or lack thereof of anti erbb2 immunoagents
The FASEB Journal, 2009Co-Authors: Gennaro Riccio, Giuseppe Dalessio, Giovanni Esposito, Emanuela Leoncini, Riccardo Contu, Gianluigi Condorelli, Massimo Chiariello, Paolo Laccetti, Silvana Hrelia, Claudia De LorenzoAbstract:This study investigated potential Cardiotoxicity as exerted by Erbicin-derived-immunoagents (EDIAs), novel human anti-ErbB2 immunoagents engineered by fusion of a human anti-ErbB2 scFv, Erbicin, with either a human RNase or the Fc region of a human IgG1. EDIAs are strongly cytotoxic on ErbB2-positive cells in vitro and in vivo and bind to an epitope different from that of Herceptin, a humanized anti-ErbB2 mAb effective in the therapy of breast carcinoma, but Cardiotoxic in a high percentage of cases. Toxicity and apoptosis were tested in vitro by 3-(4,5-dimethyl-2-thizolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), DNA fragmentation, and immunoblotting analyses. Echocardiography was measured in mice after treatment with each immunoagent. Cardiac fibrosis and detection of apoptosis were examined by Sirius red staining of collagen and TUNEL assay, respectively. EDIAs were found in vitro to have no adverse effects on cardiac cells for which Herceptin is severely toxic. In vivo studies on a mouse model showe...
Jennifer H Jordan - One of the best experts on this subject based on the ideXlab platform.
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frequency of transition from stage a to stage b heart failure after initiating potentially Cardiotoxic chemotherapy
Jacc-Heart Failure, 2018Co-Authors: Deanna N Jones, Jennifer H Jordan, Giselle C Melendez, Zanetta S Lamar, Alexandra Thomas, Dalane W Kitzman, Cynthia K Suerken, Ralph B Dagostino, Gregory W HundleyAbstract:Abstract Objectives This study sought to determine the prevalence of American Heart Association/American College of Cardiology Foundation (AHA/ACCF) heart failure (HF) stages after potentially Cardiotoxic chemotherapy was initiated. Background For individuals receiving potentially Cardiotoxic chemotherapy, the frequency of transitioning from Stage A to more advanced HF stages is not well described. Methods In 143 Stage A HF patients with breast cancer, lymphoma and leukemia, renal cell carcinoma, or sarcoma prior to and then at 3, 6, and 12 to 24 months after potentially Cardiotoxic chemotherapy was initiated, we obtained blinded cardiac magnetic resonance measurements of left ventricular ejection fraction (LVEF). Results Three months after potentially Cardiotoxic chemotherapy was initiated, 18.9% of patients transitioned from Stage A to Stage B HF. A total of 83% and 80% of patients with Stage A HF at 3 months, respectively, exhibited Stage A HF at 6 and 12 to 24 months; 68% and 56% of those with Stage B HF at 3 months, respectively, exhibited Stage B HF at 6 and 12 to 24 months (p Conclusions Transitioning from Stage A to Stage B or remaining in Stage A HF 3 months after potentially Cardiotoxic chemotherapy was initiated relates to longer-term (6 to 24 months post-treatment) assessments of HF stage.
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frequency of left ventricular end diastolic volume mediated declines in ejection fraction in patients receiving potentially Cardiotoxic cancer treatment
American Journal of Cardiology, 2017Co-Authors: Giselle C Melendez, Jennifer H Jordan, Ralph B Dagostino, Sujethra Vasu, Leslie R Ellis, Bunyapon Sukpraphrute, Heidi D Klepin, Zanetta Lamar, Glenn J Lesser, Gregory L BurkeAbstract:We sought to determine the frequency by which decreases in left ventricular (LV) end-diastolic volume (LVEDV) with and without increases in end-systolic volume (LVESV) influenced early cancer treatment-associated declines in LV ejection fraction (LVEF) or LV mass. One hundred twelve consecutively recruited subjects (aged 52 ± 14 years) with cancer underwent blinded cardiovascular magnetic resonance measurements of LV volumes, mass, and LVEF before and 3 months after initiating potentially Cardiotoxic chemotherapy (72% of participants received anthracyclines). Twenty-six participants developed important declines in LVEF of >10% or to values
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longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of Cardiotoxic chemotherapies using t1 weighted and t2 weighted cardiovascular magnetic re
Circulation-cardiovascular Imaging, 2014Co-Authors: Jennifer H Jordan, Dalane W Kitzman, Ralph B Dagostino, Craig A Hamilton, Sujethra Vasu, Michael E Hall, Vinay Thohan, Julia Lawrence, Leslie R Ellis, Timothy L LashAbstract:Background— In a murine anthracycline-related Cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially Cardiotoxic chemotherapy. Methods and Results— In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially Cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51±12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57±6% to 54±7% ( P <0.001) because of an increase in end-systolic volume ( P <0.05). T1-weighted signal intensities also increased from 14.1±5.1 to 15.9±6.8 ( P <0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment ( P =0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments ( P =0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months ( P =0.70). Conclusions— Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially Cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially Cardiotoxic chemotherapy in human subjects.
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dispersion of hyperenhancement in late gadolinium enhancement cardiovascular magnetic resonance measured with moran s i is associated with a decrement in lvef 6 months after Cardiotoxic chemotherapy
Journal of Cardiovascular Magnetic Resonance, 2013Co-Authors: Jennifer H Jordan, Ralph B Dagostino, Craig A Hamilton, Sujethra Vasu, Julia Lawrence, William Gregory HundleyAbstract:Background In animals and human subjects, an increase in background signal intensity observed on late gadolinium enhanced (LGE-SI) images is associated with a decrement in left ventricular ejection fraction (LVEF) during receipt of anthracycline chemotherapy. Moran’ sIs tatistic is a measurement of spatial dispersion of hyperenhanced voxels relative to the mean myocardial LGE-SI, ranging from highly clustered (I=+1) to highly diffuse (I=-1) (Figure 1). We hypothesize that a change in the distribution of hyperenhanced voxels (due to the development of high signal “micro clusters”) is associated with a decrement in LVEF after Cardiotoxic chemotherapy. Methods We performed a prospective, extramurally-funded longitudinal cohort study of 51 participants (43 women, 8 men; aged 52±2 years) scheduled to receive 3 to 4 months of potentially Cardiotoxic chemotherapy (anthracycline or trastuzumab) for treatment of breast cancer or hematologic malignancy. Before and then 3 and 6 months after chemotherapy initiation, participants underwent cardiovascular magnetic resonance (CMR) assessments of LVEF, LGE-SI, and Moran’s I statistic determined by personnel blinded to participant identifiers and all other aspects of the analyses. Results were analyzed using paired Student’s t-tests to test for a difference between baseline and subsequent examinations, and one-way ANOVA to test for trending change. All values are reported as mean ± standard deviation with p-values<0.05 considered statistically signficant.
Daniel Bernstein - One of the best experts on this subject based on the ideXlab platform.
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differential Cardiotoxic cardioprotective effects of β adrenergic receptor subtypes in myocytes and fibroblasts in doxorubicin cardiomyopathy
Journal of Molecular and Cellular Cardiology, 2006Co-Authors: Giovanni Fajardo, Mingming Zhao, Jennifer Powers, Daniel BernsteinAbstract:β-Adrenoceptor (β-AR) subtypes act through different signaling pathways to regulate cardiac function and remodeling. Previous in vivo data show a markedly enhanced Cardiotoxic response to doxorubicin in β2−/− mice, which is rescued by the additional deletion of the β1-AR. We determined whether this differential response was myocyte specific by examining the effects of doxorubicin in myocytes and fibroblasts from WT and β1, β2 and β1/β2−/− mice. Cells were exposed to doxorubicin at 1–50 µM and viability and apoptosis assessed at 6, 24 and 48 h. WT myocytes showed a time and dose-dependent decrease in viability (42% decrease at 1 µM after 24 h). β2−/− Myocytes showed a greater decrease in viability vs. WT (20.8% less at 6 h; 14% less at 24 h, P < 0.05); β1−/− and β1/β2−/− myocytes showed enhanced survival (β1−/− 11%; β1/β2−/− 18% greater than WT, P < 0.05). TUNEL staining demonstrated a similar differential susceptibility (WT 26% apoptotic nuclei, β2−/− 45.9%, β1/β2−/− 16.8%, P < 0.05). β2−/− Fibroblasts also showed enhanced toxicity. Pertussis toxin pretreatment of WT cells decreased survival similar to the β2−/−, suggesting a role for Gi signaling. JNK was differentially activated in β2−/− myocytes after doxorubicin and its inhibition increased Cardiotoxicity. In conclusion, the differential cardioprotective/Cardiotoxic effects mediated by β1 vs. β2-AR subtypes in knockout mice are recapitulated in myocytes isolated from these mice. β2-ARs appear to play a cardioprotective role, whereas β1-ARs a Cardiotoxic role.
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differential cardioprotective Cardiotoxic effects mediated by β adrenergic receptor subtypes
American Journal of Physiology-heart and Circulatory Physiology, 2005Co-Authors: Daniel Bernstein, Giovanni Fajardo, Mingming Zhao, Jennifer Powers, Takashi Urashima, Gerald J Berry, Brian K KobilkaAbstract:Recent data suggest that β-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of β1- vs. β2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to β1, β2, and β1/β2 knockout (−/−) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and β1−/− mice showed no acute cardiovascular effects, whereas β2−/− mice all died within 30 min. The additional deletion of the β1-receptor (β1/β2−/−) totally rescued this toxicity. β2−/− mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued β2−/− mice from this acute toxicity. The enhanced toxicity in β2−/− mice was also recapitulated in wild-type mice with the β2-selective antagonist ICI-118,551, although the rescue effect of the β1-deletion was not recapitulated using t...