Showing papers by "Donald M. Bers published in 2020"
TL;DR: The maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs should increase the fidelity of hiPSC-CMs as disease models.
170 citations
TL;DR: Diabetic hyperglycemia induces acute cardiac myocyte ROS production by NOX2 that requires O-GlcNAcylation of CaMKIIδ at S280, and this novel ROS induction may exacerbate pathological consequences of diabetic hyper glycemia.
Abstract: Rationale: Diabetes mellitus is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII (Ca2+/calmodulin-dependent kinase II) activation may occur in diabetes mellitus...
67 citations
TL;DR: The adenosine nucleotide translocase (ANT) family of proteins are inner mitochondrial membrane proteins involved in energy homeostasis and cell death and are poised to participate in several aspects of mitochondrial biology and the greater regulation of cell death.
36 citations
TL;DR: It is shown that acute hyperglycemia enhances IK1 and Ito recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces Ito amplitude via a NOX2-ROS-PKC pathway.
Abstract: Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K+ channel remodeling and increased arrhythmia risk. However, the exact signaling mechanism by which diabetic hyperglycemia regulates cardiac K+ channels remains elusive. Here, we show that acute hyperglycemia increases inward rectifier K+ current (IK1), but reduces the amplitude and inactivation recovery time of the transient outward K+ current (Ito) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, IK1 amplitude and Ito recovery effects (but not Ito amplitude) were prevented by the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, and O-GlcNAc-resistant CaMKIIδ-S280A knock-in. Ito reduction was prevented by inhibition of protein kinase C (PKC) and NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models of chronic diabetes (streptozotocin, db/db, and high-fat diet), heart failure, and CaMKIIδ overexpression, both Ito and IK1 were reduced in line with the downregulated K+ channel expression. However, IK1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances IK1 and Ito recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces Ito amplitude via a NOX2-ROS-PKC pathway. Moreover, chronic hyperglycemia during diabetes and CaMKII activation downregulate K+ channel expression and function, which may further increase arrhythmia susceptibility.
33 citations
TL;DR: Current understanding, consensus, controversies and the pressing issues for future investigations of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics are emphasized in this white paper.
Abstract: Cardiac excitation-contraction (E-C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano-electro-transduction (commonly referred to as mechano-electric coupling, MEC) and mechano-chemo-transduction (MCT) mechanisms at cell and molecular levels which couple to Ca2+ -electro and E-C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano-transduction to the Ca2+ homeodynamics and to the electrical excitation are essential for understanding the E-C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca2+ dynamics). Of course, such separation is artificial since Ca2+ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium.
30 citations
TL;DR: Whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids is determined.
29 citations
TL;DR: It is concluded that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2-CaMKII δC axis contributes to eccentric hypertrophy and HF.
Abstract: Rationale: CaMKII (Ca2+-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhyt...
29 citations
TL;DR: This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance and identifies compound concentrations that reduced leak by > 50% but only slightly affected Ca2+ release in excitation-contraction coupling, which is essential for normal muscle contraction.
Abstract: Elevated cytoplasmic [Ca2+] is characteristic in severe skeletal and cardiac myopathies, diabetes, and neurodegeneration, and partly results from increased Ca2+ leak from sarcoplasmic reticulum stores via dysregulated ryanodine receptor (RyR) channels. Consequently, RyR is recognized as a high-value target for drug discovery to treat such pathologies. Using a FRET-based high-throughput screening assay that we previously reported, we identified small-molecule compounds that modulate the skeletal muscle channel isoform (RyR1) interaction with calmodulin and FK506 binding protein 12.6. Two such compounds, chloroxine and myricetin, increase FRET and inhibit [3H]ryanodine binding to RyR1 at nanomolar Ca2+. Both compounds also decrease RyR1 Ca2+ leak in human skinned skeletal muscle fibers. Furthermore, we identified compound concentrations that reduced leak by > 50% but only slightly affected Ca2+ release in excitation-contraction coupling, which is essential for normal muscle contraction. This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance.
27 citations
TL;DR: The studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.
Abstract: Rationale: Mitochondrial Ca2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+ overload also directly causes m...
26 citations
TL;DR: IKr and INaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes, demonstrating that these ionic currents may have significant therapeutic potential in heart diseases with repolarization abnormalities.
Abstract: Background: Rapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT...
18 citations
TL;DR: A bi‐functional mechanism that restricts CaV1.2 activity to its target sites and simultaneously boosts its open probability so that CaV 1.2 is mostly active when appropriately localized.
Abstract: The L-type Ca2+ channel CaV 1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α-actinin to the IQ motif of CaV 1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV 1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1,646-1,664) bound to α-actinin-1 and to apo-calmodulin (apoCaM). The CaV 1.2 K1647A and Y1649A mutations, which impair α-actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not α-actinin-1 binding, decreased single-channel open probability, gating charge movement, and its coupling to channel opening. Thus, α-actinin recruits CaV 1.2 to defined surface regions and simultaneously boosts its open probability so that CaV 1.2 is mostly active when appropriately localized.
TL;DR: A suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species is built and its integration into mechanistic studies and drug development pipelines is suggested.
Abstract: Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, inter-species differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology, and undermine the assessment of drugs9 efficacy and safety. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca2+ transient in mouse, rabbit, and human. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and β-adrenergic challenge. We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions, and suggest its integration into mechanistic studies and drug development pipelines.
TL;DR: Turner, Matthew; Anderson, David E; Bartels, Peter; Nieves-Cintron, Madeline; Coleman, Andrea M; Henderson, Peter B; Man, Kwun Nok Mimi; Tseng, Pang-Yen; Yarov-Yarovoy, Vladimir; Bers, Donald M; Navedo, Manuel F; Horne, Mary C; Ames, James B; Hell, Johannes W
Abstract: Author(s): Turner, Matthew; Anderson, David E; Bartels, Peter; Nieves-Cintron, Madeline; Coleman, Andrea M; Henderson, Peter B; Man, Kwun Nok Mimi; Tseng, Pang-Yen; Yarov-Yarovoy, Vladimir; Bers, Donald M; Navedo, Manuel F; Horne, Mary C; Ames, James B; Hell, Johannes W
TL;DR: Before discussing the 2018 meeting content, it is wished to commemorate Dr J. Jeremy Rice, who died tragically during the conference, who was an outstanding scientist whose work on quantitative exploration of cardiac and neuronal electrophysiology, heart mechanics, and electro-mechanical coupling has lasting impact on field.
Abstract: Before discussing the 2018 meeting content, we wish to commemorate Dr J. Jeremy Rice, who died tragically during the conference. Jeremy was an outstanding scientist (member of the Faculty of 1000) whose work on quantitative exploration of cardiac and neuronal electrophysiology, heart mechanics, and electro-mechanical coupling, published in more than 75 papers, has lasting impact on our field. His true impact is much deeper than the published