Papers by D. Brian Foster
JACC. Basic to translational science, 2017
Adult stem cells demonstrate metabolic flexibility that is regulated by cell adhesion status. The... more Adult stem cells demonstrate metabolic flexibility that is regulated by cell adhesion status. The authors demonstrate that adherent cells primarily utilize glycolysis, whereas suspended cells rely on oxidative phosphorylation for their ATP needs. Akt phosphorylation transduces adhesion-mediated regulation of energy metabolism, by regulating translocation of glucose transporters (GLUT1) to the cell membrane and thus, cellular glucose uptake and glycolysis. Cell dissociation, a pre-requisite for cell transplantation, leads to energetic stress, which is mediated by Akt dephosphorylation, downregulation of glucose uptake, and glycolysis. They designed hydrogels that promote rapid cell adhesion of encapsulated cells, Akt phosphorylation, restore glycolysis, and cellular ATP levels.
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Journal of Cardiovascular Translational Research, 2011
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Biophysical Journal, 2011
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Biochemical and Biophysical Research Communications, 2008
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Experimental & Molecular Medicine, 2019
Cardiac pacemaker cells of the sinoatrial node initiate each and every heartbeat. Compared with o... more Cardiac pacemaker cells of the sinoatrial node initiate each and every heartbeat. Compared with our understanding of the constituents of their electrical excitation, little is known about the metabolic underpinnings that drive the automaticity of pacemaker myocytes. This lack is largely owing to the scarcity of native cardiac pacemaker myocytes. Here, we take advantage of induced pacemaker myocytes generated by TBX18-mediated reprogramming (TBX18-iPMs) to investigate comparative differences in the metabolic program between pacemaker myocytes and working cardiomyocytes. TBX18-iPMs were more resistant to metabolic stresses, exhibiting higher cell viability upon oxidative stress. TBX18-induced pacemaker myocytes (iPMs) expensed a lower degree of oxidative phosphorylation and displayed a smaller capacity for glycolysis compared with control ventricular myocytes. Furthermore, the mitochondria were smaller in TBX18-iPMs than in the control. We reasoned that a shift in the balance between ...
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The FASEB Journal, Apr 1, 2020
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Biophysical Journal, Feb 1, 2019
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Circulation Research, Aug 2, 2019
Objective: Cardiac troponin I (cTnI) is an essential regulator of cardiac contractility and relax... more Objective: Cardiac troponin I (cTnI) is an essential regulator of cardiac contractility and relaxation. Mutations within key regions of this regulator lead to cardiomyopathies. Further, post-translational modification of cTnI through phosphorylation impacts myofibril relaxation and calcium sensitivity. Recent studies have also demonstrated that myofibril proteins are acetylated leading to faster relaxation. These studies highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to mechanical changes in the myofibril. The objective of this study was to determine if acetylation at a single site of cTnI (lysine-132; K132) is sufficient to alter myofibril protein mechanics. Methods: Adult rat ventricular cardiomyocytes infected with adenoviral constructs expressing either cTnI K132 replaced with glutamine (K132Q; to mimic acetylation) or K132 replaced with arginine (K132R; to prevent acetylation) were subjected to cell contractility and isolated myofibril mechanic measurements. Additionally, skinned myofibrils were exchanged with troponin containing wildtype (WT) or K132Q cTnI and mechanics assessed. Finally, dynamics of reconstituted thin filaments containing WT or K132Q cTnI were assessed by in vitro motility assay. Results: Cardiomyocytes expressing cTnI K132Q relaxed faster and had decreased calcium sensitivity compared to WT cTnI at the whole cell and myofibril level. Relaxation or calcium sensitivity did not differ between cardiomyocytes infected with WT cTnI and cTnI K132R. Myofibrils with cTnI K132Q exchanged ex vivo demonstrate faster relaxation and decreased calcium sensitivity as well as decreased motility. Conclusions: Our results indicate for the first time that acetylation at a specific cTnI lysine can alter myofibril relaxation and calcium sensitivity. This work underscores the importance of understanding how acetylation affects specific sarcomeric proteins in the context of cardiac disease, and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.
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Journal of Biological Chemistry, Nov 1, 2020
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Biophysical Journal, 2015
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Journal of Molecular and Cellular Cardiology, May 1, 2015
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Communications Biology
Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart f... more Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a...
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Subject codes: [4] Acute myocardial infarction [91] Oxidant stress [131] Apoptosis [140] Energy m... more Subject codes: [4] Acute myocardial infarction [91] Oxidant stress [131] Apoptosis [140] Energy metabolism [151] Ischemic biology- basic studies [152] Ion channels/membrane transport
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Subject codes: [4] Acute myocardial infarction [91] Oxidant stress [131] Apoptosis [140] Energy m... more Subject codes: [4] Acute myocardial infarction [91] Oxidant stress [131] Apoptosis [140] Energy metabolism [151] Ischemic biology- basic studies [152] Ion channels/membrane transport
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Circulation Research, 2017
Introduction: Recently, we have investigated a pressure-overload/chronic catecholamine guinea pig... more Introduction: Recently, we have investigated a pressure-overload/chronic catecholamine guinea pig model (ACi) of cardiac hypertrophy (HYP) and HF with the unique features of acquired long QT syndrome and sudden cardiac death (SCD) by quantitative global-scale proteomics using isobaric tags for relative and absolute quantitation. Hypothesis: By compiling proteins altered significantly both compensated HYP and HF, it may be possible to identify novel early contributors to pressure overload- induced HF pathogenesis. Results: Pathway mapping of proteins differentially regulated in HYP that were also changed in HF (p<0.05 in both HYP and HF) revealed altered “retinoate biosynthesis” (p<0.01) and “RAR Activation” (p<0.05), suggesting that guinea pig HYP &HF might be related to impaired Vitamin A metabolism, specifically, to a deficit in the bioactive metabolite, all-trans retinoic acid. Causal Regulator Analysis indicated that coordinate regulation of ATRA-responsive proteins was...
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Altered Serine/Threonine phosphorylation of the cardiac proteome is an established hallmark of he... more Altered Serine/Threonine phosphorylation of the cardiac proteome is an established hallmark of heart failure (HF). However, the contribution of tyrosine phosphorylation to the pathogenesis of these diseases remains unclear. The cardiac proteome was explored by global mapping to discover and quantify site-specific tyrosine phosphorylation in two cardiac hypertrophic models; cardiac overexpression of ErbB2 (TgErbB2) and cardiac expression of α-Myosin heavy chain R403Q (R403Q-αMyHCTg) compared to control hearts. Phosphoproteomic changes found in R403Q-αMyHC Tg mice indicated EGFR1, Focal Adhesion, VEGF, ErbB signaling, and Chemokine signaling pathways activity were likely to be activated. On the other hand, TgErbB2 mice findings displayed significant overrepresentation of Right Ventricular Cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) KEGG Pathways. In silico kinase-substrate enrichment analysis (KSEA) highlighted a marked downregulation of canonic...
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Journal of Biological Chemistry, 2020
Recent proteomics studies of vertebrate striated muscle have identified lysine acetylation at sev... more Recent proteomics studies of vertebrate striated muscle have identified lysine acetylation at several sites on actin. Acetylation is a reversible post-translational modification (PTM) that neutralizes lysine’s positive charge. Actin’s positively charged residues, particularly K326 and K328, are predicted to form several, critical electrostatic interactions with tropomyosin (Tpm) that promote its binding and bias Tpm to an azimuthal location where it impedes myosin attachment. The troponin (Tn) complex also influences Tpm’s position along filamentous (F-) actin as a function of Ca2+ to regulate exposure of myosin-binding sites and, thus, myosin cross-bridge recruitment and force production. Interestingly, K326 and K328 on sarcomeric actin are among the documented acetylated residues. Using an acetic anhydride-based labeling approach, we showed that excessive, non-specific actin acetylation did not disrupt characteristic F-actin-Tpm binding. However, it significantly reduced Tpm-media...
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Journal of Molecular and Cellular Cardiology, 2020
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Circulation research, Jan 13, 2018
Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain lim... more Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been explored. We will test the hypothesis that elevated mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. Using a unique guinea pig model of non-ischemic HF that recapitulates important features of human HF, including prolonged QT interval and high incidence of spontaneous arrhythmic SCD. Compartment-specific ROS sensors revealed increased mROS in resting and contracting left ventricular (LV) myocytes in failing hearts. Importantly, mitochondrially-ta...
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Archives of biochemistry and biophysics, Jan 15, 2014
Protein kinase C (PKC)-mediated phosphorylation of troponin I (cTnI) at Ser42/44 is increased in ... more Protein kinase C (PKC)-mediated phosphorylation of troponin I (cTnI) at Ser42/44 is increased in heart failure. While studies in rodents demonstrated that PKC-mediated Ser42/44 phosphorylation decreases maximal force and ATPase activity, PKC incubation of human cardiomyocytes did not affect maximal force. We investigated whether Ser42/44 pseudo-phosphorylation affects force development and ATPase activity using troponin exchange in human myocardium. Additionally, we studied if pseudo-phosphorylated Ser42/44 modulates length-dependent activation of force, which is regulated by protein kinase A (PKA)-mediated cTnI-Ser23/24 phosphorylation. Isometric force was measured in membrane-permeabilized cardiomyocytes exchanged with human recombinant wild-type troponin or troponin mutated at Ser42/44 or Ser23/24 into aspartic acid (D) or alanine (A) to mimic phosphorylation and dephosphorylation, respectively. In troponin-exchanged donor cardiomyocytes experiments were repeated after PKA incuba...
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Papers by D. Brian Foster