Publications by authors named "Nanette H Bishopric"

55 Publications

Adverse Cardiovascular Events in Cancer Trials: Missing in Action?

J Am Coll Cardiol 2020 02;75(6):629-631

Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC.

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http://dx.doi.org/10.1016/j.jacc.2019.12.019DOI Listing
February 2020

Sex Differences in Science: Do We Have a Problem?

JACC Basic Transl Sci 2019 Aug 26;4(4):478-479. Epub 2019 Aug 26.

Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.

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http://dx.doi.org/10.1016/j.jacbts.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712275PMC
August 2019

Post-cardiac injury syndrome in acute myocardial infarction patients undergoing PCI: a case report and literature review.

BMC Cardiovasc Disord 2018 12 12;18(1):234. Epub 2018 Dec 12.

Department of Cardiovascular Medicine, Shenzhen Shekou People's Hospital, Shenzhen, 518067, Guangdong, China.

Background: In the era of primary percutaneous coronary intervention (PPCI), the incidence of post-cardiac injury syndrome (PCIS) in patients with acute myocardial infarction (AMI) following PPCI has become less common. However, the intrinsic pathogenesis of this medical condition remains largely uncertain. Unlike the prior reports, the present paper provides new mechanistic clues concerning the pathogenesis of PCI-related PCIS.

Case Presentation: A 45-year-old male with AMI had developed an early onset of PCIS at 3 h after PPCI. A significantly slower TIMI flow (grade ≤ 2) for the culprit arteries was observed through follow-up coronary angiography (CAG); no stent thrombosis or any significant evidence of iatrogenic trauma due the intervention procedures was found. Nevertheless, the the serum level of HsCRP showed similar variation trend as the neutrophil count and troponin T in continuous blood monitoring, which suggested a potential association between PPCI-related coronary microvascular dysfunction (CMD) and pathogenesis of PCIS.

Conclusions: The reported case had excessive inflammatory reaction and CMD resulting from cardiac ischemia-reperfusion injury in an AMI patient with risk factors of endothelial dysfunction. There exists a potential reciprocal causation between PCIS and performance of PPCI in the AMI patient who was susceptible to endothelial damage.
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http://dx.doi.org/10.1186/s12872-018-0964-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292035PMC
December 2018

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.

Genome Biol 2017 09 14;18(1):170. Epub 2017 Sep 14.

Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany.

Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases.

Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts.

Conclusions: RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.
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http://dx.doi.org/10.1186/s13059-017-1286-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598015PMC
September 2017

Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface.

JCI Insight 2017 09 7;2(17). Epub 2017 Sep 7.

Department of Medicine.

Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation.
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http://dx.doi.org/10.1172/jci.insight.91068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621875PMC
September 2017

A Growth Tonic for Heart Failure?

JACC Basic Transl Sci 2016 Dec 26;1(7):587-589. Epub 2016 Dec 26.

Miller School of Medicine at the University of Miami, Miami, Florida.

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http://dx.doi.org/10.1016/j.jacbts.2016.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113560PMC
December 2016

Erratum to: PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy.

Breast Cancer Res Treat 2016 Apr;156(2):405-6

Braman Family Breast Cancer Institute at Sylvester, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.

Erratum to: Breast Cancer Res Treat (2013),138:369–381,DOI 10.1007/s10549-012-2389-6. In the original publication of the article, the Fig. 4c and d were published erroneously. The revised Fig. 4 is given in this erratum.
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http://dx.doi.org/10.1007/s10549-016-3752-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969925PMC
April 2016

A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.

Biochim Biophys Acta 2016 02 2;1862(2):240-51. Epub 2015 Dec 2.

Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States. Electronic address:

Rationale: The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific.

Objective: To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart.

Methods And Results: MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1.

Conclusion: A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury.
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http://dx.doi.org/10.1016/j.bbadis.2015.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732518PMC
February 2016

Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2.

Circ Cardiovasc Genet 2015 Jun 3;8(3):447-456. Epub 2015 Mar 3.

Department of Clinical and Experimental Cardiology (I.C.R.M.K., P.G.P., J.B., T.T.K., A.A.M.W., C.R.B.), Department of Clinical Epidemiology, Biostatistics and Bioinformatics (I.C.R.M.K., M.W.T.T.), and Department of Clinical Genetics (N.H.), Academic Medical Center, Amsterdam, the Netherlands; ICIN (Netherlands Heart Institute) (J.B., A.A.M.W., C.R.B.), Utrecht, the Netherlands; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France (J.B., J.-J.S.); Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France (J.B., J.-J.S.); Université de Nantes, Nantes, France (J.B., J.-J.S.); Department of Medicine I, University Hospital Munich, Campus Grosshadern and Innenstadt, Ludwig-Maximilians University, Munich, Germany (M.F.S., B.M.B., S.K.); German Center for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (S.K.T.M.); Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany (S.Z., A.H., B.S., E.S.-B.); Interdisciplinary Centre for Clinical Research (IZKF) of the University of Münster, Münster, Germany (S.Z., A.H., B.S., E.S.-B.); Institute of Bioinformatics and Systems Biology (A.P.), and Institute of Human Genetics (A.P., P.L., T.M.), Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany (A.P., P.L., T.M.); Department of Medicine (R.J.M., N.H.B.), Department of Molecular and Cellular Pharmacology (R.J.M., N.H.B.), and Hussmann Institute of Human Genomics (R.J.M., N.H.B.), University of Miami Miller School of Medicine, FL; Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (D.M.R.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.); and Centre Hospitalier Universitaire (CHU) Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France (J.-J.S.).

Background: Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification.

Methods And Results: We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10(-8); rs12143842, P=4.8×10(-7); and rs2880058, P=8.6×10(-7)) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10(-4)) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS(NOS1AP)) uncovered a strong linear relationship between GRS(NOS1AP) and the QTc-interval (P=4.2×10(-7)). Furthermore, patients with a GRS(NOS1AP) in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039).

Conclusions: We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770255PMC
June 2015

Association between anti-human heat shock protein-60 and interleukin-2 with coronary artery calcium score.

Heart 2015 Mar 5;101(6):436-41. Epub 2015 Jan 5.

Cardiovascular Division, University of Miami Miller School of Medicine, Miami, Florida, USA.

Introduction: Based upon evidence suggesting that concentrations of anti-heat shock protein-60 (anti-HSP60) and interleukin-2 (IL-2) are associated with atherogenesis, we tested the hypothesis that anti-HSP60 and IL-2 are associated with coronary artery calcium (CAC) score, a marker of subclinical atherosclerosis.

Methods: We evaluated 998 asymptomatic adults, age 45-84 years, without known coronary disease from the Multi-Ethnic Study of Atherosclerosis (MESA), who had anti-HSP60 measured at baseline. Tertiles of serum anti-HSP60 were evaluated. The associations of IL-2 and anti-HSP60 with CAC were assessed using multivariate analyses, with adjustments for coronary risk factors and Framingham risk score.

Results: Patients' demographics, diabetes, hypertension, obesity, or dyslipidaemia did not show differences in levels of anti-HSP60. The median (IQR) Framingham risk score was 11 (5-22), 8 (5-16), and 9 (5-18) for the first, second, and third tertiles, respectively (p=0.043). IL-2 and tumour necrosis factor α (TNF-α) were associated with increased CAC (IL-2: OR 3.70, p<0.001; TNF-α: OR 4.63, p<0.001). In multivariate regression, the highest tertiles of anti-HSP60 and IL-2 were associated with increased risk of CAC (HSP60 T3: OR 1.49, p=0.022; IL-2: OR 2.49, p<0.001). After adjustment, significant progression of CAC was observed in patients with higher baseline levels of anti-HSP60 (estimate 31.73, p=0.016) and IL-2 (estimate 34.39, p=0.024).

Conclusions: Increased concentrations of inflammatory markers (IL-2 and anti-HSP60) are associated with an increased CAC at baseline and follow-up in healthy asymptomatic adults. Future studies should be carried out to assess its association with early development of atherosclerosis.
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http://dx.doi.org/10.1136/heartjnl-2014-306649DOI Listing
March 2015

Genome-wide identification of expression quantitative trait loci (eQTLs) in human heart.

PLoS One 2014 20;9(5):e97380. Epub 2014 May 20.

Department of Experimental Cardiology, Heart Failure Research Centre, Academic Medical Center, Amsterdam, The Netherlands.

In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression. Hence, the key to unraveling the molecular mechanisms underlying these cardiac traits is to interrogate variants for association with differential transcript abundance by expression quantitative trait locus (eQTL) analysis. In this study we conducted an eQTL analysis of human heart. For a total of 129 left ventricular samples that were collected from non-diseased human donor hearts, genome-wide transcript abundance and genotyping was determined using microarrays. Each of the 18,402 transcripts and 897,683 SNP genotypes that remained after pre-processing and stringent quality control were tested for eQTL effects. We identified 771 eQTLs, regulating 429 unique transcripts. Overlaying these eQTLs with cardiac GWAS loci identified novel candidates for studies aimed at elucidating the functional and transcriptional impact of these loci. Thus, this work provides for the first time a comprehensive eQTL map of human heart: a powerful and unique resource that enables systems genetics approaches for the study of cardiac traits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028258PMC
February 2015

Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

J Am Coll Cardiol 2014 Feb 27;63(6):549-59. Epub 2013 Nov 27.

Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:

Objectives: The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

Background: A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte.

Methods: The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR⁺/⁻) mice.

Results: In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR⁺/⁻ mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR⁺/⁻ hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR⁺/⁻ myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5.

Conclusions: CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease.
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http://dx.doi.org/10.1016/j.jacc.2013.10.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926969PMC
February 2014

MicroRNA-20a constrains p300-driven myocardial angiogenic transcription by direct targeting of p300.

PLoS One 2013 13;8(11):e79133. Epub 2013 Nov 13.

Department of Medicine, Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

Objective: To characterize downstream effectors of p300 acetyltransferase in the myocardium.

Background: Acetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known.

Methods And Results: Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. Chromatin immunoprecipitation demonstrated binding of p300 to the enhancers of the angiogenic regulators Angpt1 and Egln3. Interestingly, p300 overexpression in vivo was also associated with relative upregulation of several members of the anti-angiogenic miR-17∼92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. Relative expression of most members of the 17∼92 cluster was similar in all 4 cardiac chambers and in other organs, however, significant downregulation of miR-17-3p and miR-20a occurred between 1 and 8 months of age in both wt and tg mice. The decline in expression of these microRNAs was associated with increased expression of VEGFA, a validated miR-20a target. In addition, miR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 3'UTR. In vivo transduction of p300 resulted in repression both of p300 and of p300-induced angiogenic transcripts.

Conclusion: p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827282PMC
September 2014

Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

PLoS One 2013 6;8(11):e78511. Epub 2013 Nov 6.

Cardiovascular Sciences and Genetics Research Centers, St George's University of London, London, United Kingdom.

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078511PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819377PMC
August 2014

Toward a genomic definition of aspirin resistance.

J Am Coll Cardiol 2013 Oct 10;62(14):1277-1279. Epub 2013 Jul 10.

Cardiovascular Genetics Laboratory, University of Miami Miller School of Medicine, Miami, Florida. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2013.06.024DOI Listing
October 2013

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

Nat Genet 2013 Jul 26;45(7):822-4. Epub 2013 May 26.

Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.
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http://dx.doi.org/10.1038/ng.2637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793630PMC
July 2013

PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy.

Breast Cancer Res Treat 2013 Apr 21;138(2):369-81. Epub 2013 Feb 21.

Braman Family Breast Cancer Institute at Sylvester, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

Oncogenic PI3K/mTOR activation is frequently observed in human cancers and activates cell motility via p27 phosphorylations at T157 and T198. Here we explored the potential for a novel PI3K/mTOR inhibitor to inhibit tumor invasion and metastasis. An MDA-MB-231 breast cancer line variant, MDA-MB-231-1833, with high metastatic bone tropism, was treated with a novel catalytic PI3K/mTOR inhibitor, PF-04691502, at nM doses that did not impair proliferation. Effects on tumor cell motility, invasion, p27 phosphorylation, localization, and bone metastatic outgrowth were assayed. MDA-MB-231-1833 showed increased PI3K/mTOR activation, high levels of cytoplasmic p27pT157pT198 and increased cell motility and invasion in vitro versus parental. PF-04691502 treatment, at a dose that did not affect proliferation, reduced total and cytoplasmic p27, decreased p27pT157pT198 and restored cell motility and invasion to levels seen in MDA-MB-231. p27 knockdown in MDA-MB-231-1833 phenocopied PI3K/mTOR inhibition, whilst overexpression of the phosphomimetic mutant p27T157DT198D caused resistance to the anti-invasive effects of PF-04691502. Pre-treatment of MDA-MB-231-1833 with PF-04691502 significantly impaired metastatic tumor formation in vivo, despite lack of antiproliferative effects in culture and little effect on primary orthotopic tumor growth. A further link between cytoplasmic p27 and metastasis was provided by a study of primary human breast cancers which showed cytoplasmic p27 is associated with increased lymph nodal metastasis and reduced survival. Novel PI3K/mTOR inhibitors may oppose tumor metastasis independent of their growth inhibitory effects, providing a rationale for clinical investigation of PI3K/mTOR inhibitors in settings to prevent micrometastasis. In primary human breast cancers, cytoplasmic p27 is associated with worse outcomes and increased nodal metastasis, and may prove useful as a marker of both PI3K/mTOR activation and PI3K/mTOR inhibitor efficacy.
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http://dx.doi.org/10.1007/s10549-012-2389-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608882PMC
April 2013

The virtue of just enough stress: a molecular model.

Trans Am Clin Climatol Assoc 2012 ;123:175-91; discussion 191-2

University of Miami Miller School of Medicine, PO Box 016189 (R-189), RMSB 6026, Miami, FL 33101, USA.

Molecular biology emphasizes the study of all-or-nothing phenomena and molecular events with a large dynamic range. However, many important physiologic parameters in the clinical setting are tightly constrained (e.g., serum sodium concentration, body mass, venous oxygen saturation, sleep duration). Stress responses exhibit both a wide dynamic range and a potential for important effects at a "just-enough" threshold activation level. Stress responses occur in a number of body systems (e.g., neuropsychiatric, immune, cardiovascular) and are essential for short-term damage control, but also must be tightly constrained in range and duration to permit the organism to walk the narrow homeostatic path to long-term survival. Using an example of a newly appreciated stress-responsive molecule in the heart, acetyltransferase p300, as well as examples from the literature, this article discusses the advantages of self-limited stress, the adverse effects of sustained stress, and the built-in mechanisms that feed back on and terminate stress signals, and advances a hypothesis regarding stress as a pharmacological target in the heart.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540631PMC
July 2013

Dysfunctional potassium channel subunit interaction as a novel mechanism of long QT syndrome.

Heart Rhythm 2013 May 2;10(5):728-37. Epub 2013 Jan 2.

Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.

Background: The slowly-activating delayed rectifier current IKs contributes to repolarization of the cardiac action potential, and is composed of a pore-forming α-subunit, KCNQ1, and a modulatory β-subunit, KCNE1. Mutations in either subunit can cause long QT syndrome, a potentially fatal arrhythmic disorder. How KCNE1 exerts its extensive control over the kinetics of IKs remains unresolved

Objective: To evaluate the impact of a novel KCNQ1 mutation on IKs channel gating and kinetics

Methods: KCNQ1 mutations were expressed in Xenopus oocytes in the presence and absence of KCNE1. Voltage clamping and MODELLER software were used to characterize and model channel function. Mutant and wt genes were cloned into FLAG, Myc and HA expression vectors to achieve differential epitope tagging, and expressed in HEK293 cells for immunohistochemical localization and surface biotinylation assay.

Results: We identified 2 adjacent mutations, S338F and F339S, in the KCNQ1 S6 domain in unrelated probands. The novel KCNQ1 S338F mutation segregated with prolonged QT interval and torsade de pointes; the second variant, F339S, was associated with fetal bradycardia and prolonged QT interval, but no other clinical events. S338F channels expressed in Xenopus oocytes had slightly increased peak conductance relative to wild type, with a more positive activation voltage. F339S channels conducted minimal current. Unexpectedly, S338F currents were abolished by co-expression with intact WT KCNE1 or its C-terminus (aa63-129), despite normal membrane trafficking and surface co-localization of KCNQ1 S338F and wt KCNE1. Structural modeling indicated that the S338F mutation specifically alters the interaction between the S6 domain of one KCNQ1 subunit and the S4-S5 linker of another, inhibiting voltage-induced movement synergistically with KCNE1 binding.

Conclusions: A novel KCNQ1 mutation specifically impaired channel function in the presence of KCNE1. Our structural model shows that this mutation effectively immobilizes voltage gating by an inhibitory interaction that is additive with that of KCNE1. Our findings illuminate a previously unreported mechanism for LQTS, and validate recent theoretical models of the closed state of the KCNQ1:KCNE1 complex.
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http://dx.doi.org/10.1016/j.hrthm.2012.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770260PMC
May 2013

Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival.

Breast Cancer Res Treat 2012 Aug 5;135(1):103-14. Epub 2012 May 5.

Departments of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.

The nuclear acetyltransferase p300 is rapidly and stably induced in the heart during hemodynamic stress, but the mechanism of this induction is unknown. To determine the role of oxidative stress in p300 induction, we exposed neonatal rat cardiac myocytes to doxorubicin (DOX, 1 μM) or its vehicle, and monitored p300 protein content and stability for 24 h. Levels of p300 rose substantially within 1 h and remained elevated for at least 24 h, while p300 transcript levels declined. In the presence of cycloheximide, the estimated half-life of p300 in control cells was approximately 4.5 h, typical of an immediate-early response protein. DOX treatment prolonged p300 t(1/2) to >24 h, indicating that the sharp rise in p300 levels was attributable to rapid protein stabilization. p300 stabilization was entirely due to an increase in acetylated p300 species with greatly enhanced resistance to proteasomal degradation. The half-life of p300 was dependent on its acetyltransferase activity, falling in the presence of p300 inhibitors curcumin and anacardic acid, and increasing with histone deacetylase (HDAC) inhibition. At the same time, acetyl-STAT3, phospho-STAT3-(Tyr 705) and -(Ser 727) increased, together with a prolongation of STAT3 half-life. SiRNA-mediated p300 knockdown abrogated all of these effects, and strongly enhanced DOX-mediated myocyte apoptosis. We conclude that DOX induces an acute amplification of p300 levels through auto-acetylation and stabilization. In turn, elevated p300 provides a key defense against acute oxidative stress in cardiac myocytes by acetylation, activation, and stabilization of STAT3. Our results suggest that HDAC inhibitors could potentially reduce acute anthracycline-mediated cardiotoxicity by promoting p300 auto-acetylation.
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http://dx.doi.org/10.1007/s10549-012-2069-6DOI Listing
August 2012

Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy.

EMBO Mol Med 2012 Jul 24;4(7):617-32. Epub 2012 Apr 24.

Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.

An increase in cardiac workload, ultimately resulting in hypertrophy, generates oxidative stress and therefore requires the activation of both survival and growth signal pathways. Here, we wanted to characterize the regulators, targets and mechanistic roles of miR-142, a microRNA (miRNA) negatively regulated during hypertrophy. We show that both miRNA-142-3p and -5p are repressed by serum-derived growth factors in cultured cardiac myocytes, in models of cardiac hypertrophy in vivo and in human cardiomyopathic hearts. Levels of miR-142 are inversely related to levels of acetyltransferase p300 and MAPK activity. When present, miR-142 inhibits both survival and growth pathways by directly targeting nodal regulators p300 and gp130. MiR-142 also potently represses multiple components of the NF-κB pathway, preventing cytokine-mediated NO production and blocks translation of α-actinin. Forced expression of miR-142 during hypertrophic growth induced extensive apoptosis and cardiac dysfunction; conversely, loss of miR-142 fully rescued cardiac function in a murine heart failure model. Downregulation of miR-142 is required to enable cytokine-mediated survival signalling during cardiac growth in response to haemodynamic stress and is a critical element of adaptive hypertrophy.
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http://dx.doi.org/10.1002/emmm.201200234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407949PMC
July 2012

A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.

Circ Cardiovasc Genet 2012 Feb 18;5(1):91-9. Epub 2011 Nov 18.

Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians University, Munich, Germany.

Background: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS.

Methods And Results: In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects.

Conclusions: This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
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http://dx.doi.org/10.1161/CIRCGENETICS.111.960930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288202PMC
February 2012

Heterogeneity in SDF-1 expression defines the vasculogenic potential of adult cardiac progenitor cells.

PLoS One 2011 24;6(8):e24013. Epub 2011 Aug 24.

Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, United States of America.

Rationale: The adult myocardium has been reported to harbor several classes of multipotent progenitor cells (CPCs) with tri-lineage differentiation potential. It is not clear whether c-kit+CPCs represent a uniform precursor population or a more complex mixture of cell types.

Objective: To characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations.

Methods And Results: c-kit+, sca-1+ CPCs obtained from adult mouse left ventricle expressed stem cell-associated genes, including Oct-4 and Myc, and were self-renewing, pluripotent and clonogenic. Detailed single cell clonal analysis of 17 clones revealed that most (14/17) exhibited trilineage differentiation potential. However, striking morphological differences were observed among clones that were heritable and stable in long-term culture. 3 major groups were identified: round (7/17), flat or spindle-shaped (5/17) and stellate (5/17). Stellate morphology was predictive of vasculogenic differentiation in Matrigel. Genome-wide expression studies and bioinformatic analysis revealed clonally stable, heritable differences in stromal cell-derived factor-1 (SDF-1) expression that correlated strongly with stellate morphology and vasculogenic capacity. Endogenous SDF-1 production contributed directly to vasculogenic differentiation: both shRNA-mediated knockdown of SDF-1 and AMD3100, an antagonist of the SDF-1 receptor CXC chemokine Receptor-4 (CXCR4), reduced tube-forming capacity, while exogenous SDF-1 induced tube formation by 2 non-vasculogenic clones. CPCs producing SDF-1 were able to vascularize Matrigel dermal implants in vivo, while CPCs with low SDF-1 production were not.

Conclusions: Clonogenic c-kit+, sca-1+ CPCs are heterogeneous in morphology, gene expression patterns and differentiation potential. Clone-specific levels of SDF-1 expression both predict and promote development of a vasculogenic phenotype via a previously unreported autocrine mechanism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161114PMC
February 2012

Inflammation, stem cells and atherosclerosis genetics.

Curr Opin Mol Ther 2010 Dec;12(6):712-23

University of Miami Leonard M Miller School of Medicine, Department of Medicine, Rosenstiel Medical Science Building, 1600 NW 10th Avenue, Miami, FL 33136, USA.

Atherosclerosis and its associated complications remain the primary cause of death in humans. Aging is the main contributor to atherosclerosis, compared with any other risk factor, yet the specific manner in which age increases risk (the 'aging-risk' mechanism) remains elusive. A novel concept for atherosclerosis risk implicates a lack of endothelial progenitor cell (EPC)-dependent arterial repair in the development of the disease that is secondary to exhaustion of repair-competent EPCs. Molecular evidence derived from genetic techniques indicates atherosclerotic lesions may begin to form as arterial repair fails, rather than merely following arterial injury. Thus, chronic arterial injury may overwhelm the ability of EPCs to maintain arterial homeostasis, particularly when EPCs capable of arterial repair become exhausted. Recent studies have reported genes identified using non-biased approaches (ie, genetic linkage studies and genome-wide association studies) that are associated with susceptibility for atherosclerosis and related thromboembolic disorders; these genes may be implicated in the control of arterial wall inflammation and EPC-mediated tissue repair. Most of the genes identified by using non-biased genomic techniques are associated with inflammation, immune response and stem cells. This review focuses on new genetic data in the field of atherosclerosis and arterial homeostasis.
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December 2010

Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction.

Nat Genet 2010 Aug 11;42(8):688-691. Epub 2010 Jul 11.

Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47-2.13, P = 3.3 x 10(-10)). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.
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http://dx.doi.org/10.1038/ng.623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966292PMC
August 2010

Comparison of microsomal prostaglandin E synthase-1 deletion and COX-2 inhibition in acute cardiac ischemia in mice.

Prostaglandins Other Lipid Mediat 2009 Nov 25;90(1-2):21-5. Epub 2009 Jun 25.

Department of Research, Division of Neonatology, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, USA.

The aim of the present study was to compare the effects of genetic mPGES-1 loss and COX-2 inhibition on myocardial damage after coronary occlusion. mPGES-1(-/-) mice and their wild-type littermates were injected with vehicle or COX-2 inhibitor (celecoxib), and 30min later the left coronary artery was surgically occluded. At 24h, myocardial infarct (MI) volume was measured histologically. Post-MI survival was reduced in WT mice receiving celecoxib (12/20) compared with vehicle-treated controls (12/12) or the loss of mPGES-1 (13/13) together with increased phosphokinase (CPK) and cardiac troponin-I release. Endogenous mPGES-1 expression was unchanged by ischemia in WT mice and absent in mPGES-1(-/-) hearts. COX-2 expression was markedly increased at 24h after MI in WT hearts; this upregulation was largely attenuated in mPGES-1(-/-) mice. We conclude that loss of mPGES-1 prevents the upregulation of COX-2 after myocardial infarct, and in contrast to inhibition of COX-2, does not increase ischemic myocardial damage.
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http://dx.doi.org/10.1016/j.prostaglandins.2009.06.006DOI Listing
November 2009

The effects of microsomal prostaglandin E synthase-1 deletion in acute cardiac ischemia in mice.

Prostaglandins Leukot Essent Fatty Acids 2009 Jul 12;81(1):31-3. Epub 2009 Jun 12.

Department of Research, Division of Neonatology, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, USA.

The goal of the present study was to assess how genetic loss of microsomal prostaglandin E(2) synthase-1 (mPGES-1) affects acute cardiac ischemic damage after coronary occlusion in mice. Wild type (WT), heterozygous (mPGES-1(+/-)), and homozygous (mPGES-1(-/-)) knockout mice were subjected to left coronary artery occlusion. At 24h, myocardial infarct (MI) volume was measured histologically. Post-MI survival, plasma levels of creatine phosphokinase (CPK) and cardiac troponin-I, together with MI size, were similar in WT, mPGES-1(+/-) and mPGES-1(-/-) mice. In contrast, post-MI survival was reduced in mPGES-1(-/-) mice pretreated with I prostanoid receptor (IP) antagonist (12/16) compared with vehicle-treated controls (13/13 mPGES-1(-/-)) together with increased CPK and cardiac troponin-I release. The deletion of mPGES-1 in mice results in increased prostacyclin I(2) (PGI(2)) formation and marginal effects on the circulatory prostaglandin E(2) (PGE(2)) level. We conclude that loss of mPGES-1 results in increased PGI(2) formation, and in contrast to inhibition of PGI(2), without worsening acute cardiac ischemic injury.
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http://dx.doi.org/10.1016/j.plefa.2009.05.019DOI Listing
July 2009

Dilated cardiomyopathy with increased SR Ca2+ loading preceded by a hypercontractile state and diastolic failure in the alpha(1C)TG mouse.

PLoS One 2009 6;4(1):e4133. Epub 2009 Jan 6.

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA.

Mice over-expressing the alpha(1)_subunit (pore) of the L-type Ca2+ channel (alpha(1C)TG) by 4 months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load. With advancing age (8-11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG),while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2-4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanodine receptor protein levels and phosphorylation become reduced. In FTG, the SR Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca2+ loading or release, as occurs in some other cardiomyopathic models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607013PMC
February 2009

Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.

Circulation 2008 Aug 12;118(9):934-46. Epub 2008 Aug 12.

University of Miami School of Medicine, Department of Molecular and Cellular Pharmacology, Miami, FL, USA.

Background: Acetyltransferase p300 is essential for cardiac development and is thought to be involved in cardiac myocyte growth through MEF2- and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown.

Methods And Results: Pressure overload induced by transverse aortic coarctation, postnatal physiological growth, and human heart failure were associated with large increases in p300. Minimal transgenic overexpression of p300 (1.5- to 3.5-fold) induced striking myocyte and cardiac hypertrophy. Both mortality and cardiac mass were directly related to p300 protein dosage. Heterozygous loss of a single p300 allele reduced pressure overload-induced hypertrophy by approximately 50% and rescued the hypertrophic phenotype of p300 overexpressers. Increased p300 expression had no effect on total histone deacetylase activity but was associated with proportional increases in p300 acetyltransferase activity and acetylation of the p300 substrates histone 3 and GATA-4. Remarkably, a doubling of p300 levels was associated with the de novo acetylation of MEF2. Consistent with this, genes specifically upregulated in p300 transgenic hearts were highly enriched for MEF2 binding sites.

Conclusions: Small increments in p300 are necessary and sufficient to drive myocardial hypertrophy, possibly through acetylation of MEF2 and upstream of signals promoting phosphorylation or nuclear export of histone deacetylases. We propose that induction of myocardial p300 content is a primary rate-limiting event in the response to hemodynamic loading in vivo and that p300 availability drives and constrains adaptive myocardial growth. Specific reduction of p300 content or activity may diminish stress-induced hypertrophy and forestall the development of heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.107.760488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726266PMC
August 2008