Jeffery D Molkentin

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (353)3170.46 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Sarcolipin (SLN) is a regulator of sarco(endo)plasmic reticulum calcium ATPase (SERCA) in skeletal muscle. Recent studies using SLN null mice have identified SLN as a key player in muscle thermogenesis and metabolism. In this study, we exploited a SLN overexpression (Sln(OE)) mouse model to determine whether increased SLN level affected muscle contractile properties, exercise capacity/ fatigue and metabolic rate in whole animals and isolated muscle. We found that Sln(OE) mice are more resistant to fatigue and can run significantly longer distance than wild type (WT). Studies with isolated extensor digitorum longus (EDL) muscle show that Sln(OE) EDL produces higher twitch force than WT. The force-frequency curves were not different between WT and Sln(OE) EDLs, but at lower frequencies the pyruvate induced potentiation of force was significantly higher in Sln(OE) EDL. SLN overexpression did not alter the twitch and force frequency curve in isolated soleus muscle. However, during a 10 minute fatigue protocol both EDL and soleus from Sln(OE) mice fatigued significantly less than WT muscles. Interestingly, Sln(OE) muscles showed higher carnitine palmitoyl transferase-1 protein expression, which could enhance fatty acid metabolism. In addition, lactate dehydrogenase expression was higher in Sln(OE) EDL suggesting increased glycolytic capacity. We also found an increase in store operated calcium entry (SOCE), in isolated flexor digitorum brevis fibers of Sln(OE) than WT mice. These data allow us to conclude that increased SLN expression improves skeletal muscle performance during prolonged muscle activity, by increasing SOCE and muscle energetics. Copyright © 2014, Journal of Applied Physiology.
    Journal of applied physiology (Bethesda, Md. : 1985). 02/2015;
  • Jennifer Q Kwong, Jeffery D Molkentin
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    ABSTRACT: Prolonged mitochondrial permeability transition pore (MPTP) opening results in mitochondrial energetic dysfunction, organelle swelling, rupture, and typically a type of necrotic cell death. However, acute opening of the MPTP has a critical physiologic role in regulating mitochondrial Ca(2+) handling and metabolism. Despite the physiological and pathological roles that the MPTP orchestrates, the proteins that comprise the pore itself remain an area of ongoing investigation. Here, we will discuss the molecular composition of the MPTP and its role in regulating cardiac physiology and disease. A better understanding of MPTP structure and function will likely suggest novel cardioprotective therapeutic approaches. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 02/2015; 21(2):206-214. · 16.75 Impact Factor
  • Jop H van Berlo, Jeffery D Molkentin
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    ABSTRACT: Cardiac regeneration is a rapidly evolving and controversial field of research. The identification some 12 years ago of progenitor cells that reside within the heart spurred enthusiasm for cell-based regenerative therapies. However, recent evidence has called into question both the presence of a biologically important stem cell population in the heart and the ability of exogenously derived cells to promote regeneration through direct formation of new cardiomyocytes. Here, we discuss recent developments that suggest an emerging consensus on the ability of different cell types to regenerate the adult mammalian heart.
    Nature Medicine 12/2014; 20(12):1386-93. · 28.05 Impact Factor
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    ABSTRACT: Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.
    Science translational medicine 10/2014; 6(259):259ra144. · 14.41 Impact Factor
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    ABSTRACT: The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)-a procedure that induces pressure overload and, if prolonged, heart failure-exhibited a similar amount of hypertrophy as those of the wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than those from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardioprotective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis).
    Science Signaling 10/2014; 7(348):ra100. · 7.65 Impact Factor
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    ABSTRACT: -Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown.
    Circulation 10/2014; · 14.95 Impact Factor
  • Jeffery D Molkentin
    Circulation Research 09/2014; 115(8):e21-3. · 11.09 Impact Factor
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    ABSTRACT: Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-β has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFβ-dependent pathology have not been segregated. Here we generated transgenic mice with myofiber-specific inhibition of TGFβ signaling due to expression of a TGFβ type II receptor dominant negative (dnTGFβRII) truncation mutant. Expression of dnTGFβRII in myofibers mitigated the dystrophic phenotype observed in δ-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGFβRII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGFβRII mediated protection, one of which was induction of the antioxidant proteins metallothionein (Mt). Indeed, TGFβ directly inhibited Mt gene expression in vitro, the dnTGFβRII transgene conferred protection against ROS accumulation in dystrophic muscle, and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGFβ signaling in MD.
    Human Molecular Genetics 08/2014; · 6.68 Impact Factor
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    ABSTRACT: Rationale: The cellular and molecular basis for post myocardial infarction (MI) structural and functional remodeling is not well understood. Objective: To determine if Ca(2+) influx through transient receptor potential (canonical) (TRPC) channels contributes to post-MI structural and functional remodeling. Methods and Results: TRPC1/3/4/6 channel mRNA increased after MI in mice and was associated with TRPC-mediated Ca(2+) entry. Cardiac myocyte specific expression of a dominant negative (dn: loss of function) TRPC4 channel increased basal myocyte contractility and reduced hypertrophy and cardiac structural and functional remodeling after MI while increasing survival. We used adenovirus-mediated expression of TRPC3/4/6 channels in cultured adult feline myocytes (AFMs) to define mechanistic aspects of these TRPC-related effects. TRPC3/4/6 over expression in AFMs induced calcineurin (Cn)-Nuclear Factor of Activated T cells (NFAT) mediated hypertrophic signaling, which was reliant on caveolae targeting of TRPCs. TRPC3/4/6 expression in AFMs increased rested state contractions and increased spontaneous sarcoplasmic reticulum (SR) Ca(2+) sparks mediated by enhanced phosphorylation of the ryanodine receptor. TRPC3/4/6 expression was associated with reduced contractility and response to catecholamines during steady state pacing, likely due to enhanced SR Ca(2+) leak. Conclusions: Ca(2+) influx through TRPC channels expressed after MI activates pathological cardiac hypertrophy and reduces contractility reserve. Blocking post-MI TRPC activity improved post-MI cardiac structure and function.
    Circulation Research 07/2014; · 11.09 Impact Factor
  • Jason Karch, Jeffery D Molkentin
    Proceedings of the National Academy of Sciences 07/2014; · 9.81 Impact Factor
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    ABSTRACT: Muscular dystrophies are a group of genetic diseases that lead to muscle wasting and in most cases, premature death. Cytokines and inflammatory factors are released during the disease process where they promote deleterious signaling events that directly participate in myofiber death. Here we show that p38α, a kinase in the greater mitogen-activated protein kinase (MAPK) signaling network, serves as a nodal regulator of disease signaling in dystrophic muscle. Deletion of Mapk14 (p38α encoding gene) in the skeletal muscle of mdx (lacking dystrophin) or sgcd (δ-sarcoglycan encoding gene) null mice resulted in a significant reduction in pathology up to 6 months of age. We also generated MAPK kinase 6 (MKK6) muscle-specific transgenic mice to model heightened p38α disease signaling that occurs in dystrophic muscle, which resulted in severe myofiber necrosis and many hallmarks of muscular dystrophy. Mechanistically, we show that p38α directly induces myofiber death through a mitochondrial-dependent pathway involving direct phosphorylation and activation of the pro-death Bcl-2 family member Bax. Indeed, muscle-specific deletion of Bax, but not the apoptosis regulatory gene Tp53 (encoding p53), significantly reduced dystrophic pathology in the muscles of MKK6 transgenic mice. Moreover, use of a p38 MAPK pharmacologic inhibitor reduced dystrophic disease in Sgcd(-/-) mice suggesting a future therapeutic approach to delay disease.
    Human Molecular Genetics 05/2014; · 6.68 Impact Factor
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    ABSTRACT: If and how the heart regenerates after an injury event is highly debated. c-kit-expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit(+) cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit(+) cells amply generated cardiac endothelial cells. Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.
    Nature 05/2014; · 42.35 Impact Factor
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    ABSTRACT: The Mitochondrial Permeability Transition (MPT) pore is a voltage-sensitive unselective channel known to instigate necrotic cell death during cardiac disease. Recent models suggest that the isomerase cyclophilin D (CypD) regulates the MPT pore by binding to either the F0F1-ATP synthase lateral stalk or the mitochondrial phosphate carrier (PiC). Here we confirm that CypD, through its N-terminus, can directly bind PiC. We then generated cardiac-specific mouse strains overexpressing or with decreased levels of mitochondrial PiC to assess the functionality of such interaction. While PiC overexpression had no observable pathologic phenotype, PiC knockdown resulted in cardiac hypertrophy along with decreased ATP levels. Mitochondria isolated from hearts of these mouse lines and their respective non-transgenic controls had no divergent phenotype in terms of oxygen consumption and Ca(2+)-induced MPT, as assessed by swelling and Ca(2+)-retention measurements. These results provide genetic evidence indicating that the mitochondrial PiC is not a critical component of the MPT pore.
    Journal of Molecular and Cellular Cardiology 04/2014; · 5.15 Impact Factor
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    ABSTRACT: Unregulated Ca(2+) entry is thought to underlie muscular dystrophy. Here we generated skeletal muscle-specific transgenic mice expressing the Na(+)/Ca(2+) exchanger 1 (NCX1) to model its known augmentation during muscular dystrophy. The NCX1 transgene induced dystrophic-like disease in all hindlimb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd(-/-)), Dysf(-/-), and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hindlimb pathology in Sgcd(-/-) mice. Measured increases in baseline Na(+) and Ca(2+) in dystrophic muscle fibers of the hindlimb musculature predicts a net Ca(2+) influx state due to reverse mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward mode NCX1 operation that reduces Ca(2+) levels. Indeed, Atp1a2(+/-) (encodes Na(+)/K(+) ATPase α2) mice, which have reduced Na(+) clearance rates that would favor NCX1 reverse mode operation, showed exacerbated disease in the hindlimbs of NCX1 TG mice, similar to treatment with the Na(+)/K(+) ATPase inhibitor digoxin. Treatment of Sgcd(-/-) mice with ranolazine, a broadly acting Na(+) channel inhibitor that should increase NCX1 forward mode operation, reduced muscular pathology.
    Molecular and Cellular Biology 03/2014; · 5.04 Impact Factor
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    ABSTRACT: The mitochondrial phosphate carrier (PiC) is critical for ATP synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. In addition to its role in energy production, PiC is hypothesized to have a role in cell death as either a component or a regulator of the mitochondrial permeability transition pore (MPTP) complex. Here, we have generated a mouse model with inducible and cardiac-specific deletion of the Slc25a3 gene (PiC protein). Loss of PiC protein did not prevent MPTP opening, suggesting it is not a direct pore-forming component of this complex. However, Slc25a3 deletion in the heart blunted MPTP opening in response to Ca(2+) challenge and led to a greater Ca(2+) uptake capacity. This desensitization of MPTP opening due to loss or reduction in PiC protein attenuated cardiac ischemic-reperfusion injury, as well as partially protected cells in culture from Ca(2+) overload induced death. Intriguingly, deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3. Together, these results demonstrate that although the PiC is not a direct component of the MPTP, it can regulate its activity, suggesting a novel therapeutic target for reducing necrotic cell death. In addition, mice lacking Slc25a3 in the heart serve as a novel model of metabolic, mitochondrial-driven cardiomyopathy.Cell Death and Differentiation advance online publication, 21 March 2014; doi:10.1038/cdd.2014.36.
    Cell death and differentiation 03/2014; · 8.24 Impact Factor
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    ABSTRACT: Wound healing after myocardial infarction involves a highly regulated inflammatory response that is initiated by the appearance of neutrophils to clear out dead cells and matrix debris. Neutrophil infiltration is controlled by multiple secreted factors, including the master regulator transforming growth factor beta (TGFβ). Broad inhibition of TGFβ early post-infarction has worsened post-MI remodeling; however, this signaling displays potent cell-specificity and targeted suppression particularly in the myocyte could be beneficial. To test the hypothesis that targeted suppression of myocyte TGFβ signaling suppresses post-infarct remodeling and inflammatory modulation, and identify mechanisms by which this may be achieved. Mice with TGFβ receptor-coupled signaling genetically suppressed only in cardiac myocytes (conditional TGFβ receptor 1 or 2 knockout) displayed marked declines in neutrophil recruitment and accompanying metalloproteinase-9 activation after infarction, and were protected against early onset mortality due to wall rupture. This was a cell-specific effect, as broader inhibition of TGFβ signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing generation of pro-inflammatory cytokines/chemokines, myocyte-selective TGFβ-inhibition augmented synthesis of a constellation of highly protective cardiokines. These included thrombospondin 4 with associated endoplasmic reticulum stress responses, interleukin-33, follistatin-like 1, and growth and differentiation factor-15 (GDF-15), which is an inhibitor of neutrophil integrin activation and tissue migration. These data reveal a novel role of myocyte canonical TGFβ signaling as a potent regulator of protective cardiokine and neutrophil mediated infarct remodeling.
    Circulation Research 02/2014; · 11.09 Impact Factor
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    ABSTRACT: Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca(2+) influx into myofibers leading to their death. Store-operated Ca(2+) entry (SOCE) through sarcolemmal Ca(2+) selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca(2+) entry. Here we generated a mouse model of STIM1 overexpression in skeletal muscle to determine if this type of Ca(2+) entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in store-operated Ca(2+) entry in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan deficient mouse models of disease. Hence, Ca(2+) influx across an unstable sarcolemma due to increased activity of a STIM1-Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
    Human Molecular Genetics 02/2014; · 6.68 Impact Factor
  • Jeffery D Molkentin, Steven R Houser
    Circulation Research 02/2014; 114(4):e27. · 11.09 Impact Factor
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    ABSTRACT: The Mitochondrial Permeability Transition (MPT) pore is a voltage-sensitive unselective channel known to instigate necrotic cell death during cardiac disease. Recent models suggest that the isomerase cyclophilin D (CypD) regulates the MPT pore by binding to either the F0F1-ATP synthase lateral stalk or the mitochondrial phosphate carrier (PiC). Here we confirm that CypD, through its N-terminus, can directly bind PiC. We then generated cardiac-specific mouse strains overexpressing or with decreased levels of mitochondrial PiC to assess the functionality of such interaction. While PiC overexpression had no observable pathologic phenotype, PiC knockdown resulted in cardiac hypertrophy along with decreased ATP levels. Mitochondria isolated from hearts of these mouse lines and their respective non-transgenic controls had no divergent phenotype in terms of oxygen consumption and Ca2 +-induced MPT, as assessed by swelling and Ca2 +-retention measurements. These results provide genetic evidence indicating that the mitochondrial PiC is not a critical component of the MPT pore.
    Journal of Molecular and Cellular Cardiology 01/2014; · 5.22 Impact Factor
  • Jop H van Berlo, Bruce J Aronow, Jeffery D Molkentin
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    ABSTRACT: The transcriptional code that programs cardiac hypertrophy involves the zinc finger-containing DNA binding factors GATA-4 and GATA-6, both of which are required to mount a hypertrophic response of the adult heart. Here we performed conditional gene deletion of Gata4 or Gata6 in the mouse heart in conjunction with reciprocal gene replacement using a transgene encoding either GATA-4 or GATA-6 in the heart as a means of parsing dosage effects of GATA-4 and GATA-6 versus unique functional roles. We determined that GATA-4 and GATA-6 play a redundant and dosage-sensitive role in programming the hypertrophic growth response of the heart following pressure overload stimulation. However, non-redundant functions were identified in allowing the heart to compensate and resist heart failure after pressure overload stimulation, as neither Gata4 nor Gata6 deletion was fully rescued by expression of the reciprocal transgene. For example, only Gata4 heart-specific deletion blocked the neoangiogenic response to pressure overload stimulation. Gene expression profiling from hearts of these gene-deleted mice showed both overlapping and unique transcriptional codes, which is presented. These results indicate that GATA-4 and GATA-6 play a dosage-dependent and redundant role in programming cardiac hypertrophy, but that each has a more complex role in maintaining cardiac homeostasis and resistance to heart failure following injury that cannot be compensated by the other.
    PLoS ONE 12/2013; 8(12):e84591. · 3.53 Impact Factor
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Publication Stats

25k Citations
3,170.46 Total Impact Points

Institutions

  • 2009–2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Duke University
      Durham, North Carolina, United States
    • Washington University in St. Louis
      • Center for Pharmacogenomics
      Saint Louis, MO, United States
    • Indiana University-Purdue University School of Medicine
      • Wells Center for Pediatric Research
      Indianapolis, Indiana, United States
    • University of Maryland, Baltimore
      • Department of Physiology
      Baltimore, Maryland, United States
  • 2000–2014
    • University of Cincinnati
      • • Department of Pediatrics
      • • Department of Molecular and Cellular Physiology
      Cincinnati, Ohio, United States
  • 1998–2014
    • Cincinnati Children's Hospital Medical Center
      • • Division of Molecular Cardiovascular Biology
      • • Department of Pediatrics
      Cincinnati, Ohio, United States
  • 2008–2012
    • Temple University
      • Department of Physiology
      Filadelfia, Pennsylvania, United States
  • 2006–2012
    • University of Washington Seattle
      • Department of Physiology and Biophysics
      Seattle, WA, United States
  • 2011
    • Loyola University Chicago
      • Department of Cell and Molecular Physiology
      Chicago, IL, United States
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, New York, United States
  • 1996–2011
    • University of Texas Southwestern Medical Center
      • Department of Molecular Biology
      Dallas, Texas, United States
    • University of Texas MD Anderson Cancer Center
      • Department of Biochemistry and Molecular Biology
      Houston, TX, United States
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 2009–2010
    • University of Bristol
      • School of Physiology and Pharmacology
      Bristol, ENG, United Kingdom
  • 2002–2009
    • Hannover Medical School
      • Department of Cardiology and Angiology
      Hanover, Lower Saxony, Germany
  • 2007
    • Albany Medical College
      • Center for Immunology and Microbial Disease
      Albany, New York, United States
    • University of Oslo
      Kristiania (historical), Oslo, Norway
  • 2002–2007
    • University of Toronto
      • • Heart and Stroke/Richard Lewar Centre of Excellencein Cardiovascular Research
      • • Division of Cardiology
      Toronto, Ontario, Canada
  • 2004
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
    • Boston University
      • Department of Medicine
      Boston, MA, United States
  • 2003
    • Tufts University
      • Molecular Cardiology Research Institute (MCRI)
      Medford, MA, United States
  • 2001
    • Massachusetts General Hospital
      • Division of Cardiology
      Boston, MA, United States
  • 1994
    • Medical College of Wisconsin
      • Department of Physiology
      Milwaukee, WI, United States