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Free Radical Biology & Medicine Oct 2023High levels of circulating catecholamines cause cardiac injury, pathological remodeling, and heart failure, but the underlying mechanisms remain elusive. Here we provide...
High levels of circulating catecholamines cause cardiac injury, pathological remodeling, and heart failure, but the underlying mechanisms remain elusive. Here we provide both in vitro and in vivo evidence that excessive β-adrenergic stimulation induces ferroptosis in cardiomyocytes, revealing a novel mechanism for catecholamine-induced cardiotoxicity and remodeling. We found that isoproterenol, a synthetic catecholamine, promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to GPX4 inactivation and enhanced lipid peroxidation. Isoproterenol also promoted heme oxygenase 1 (HO-1) expression by downregulating the transcription suppressor BTB and CNC homology 1 (Bach1), leading to increased labile iron accumulation through heme degradation. Moreover, isoproterenol markedly induced the accumulation of free iron and lipid reactive oxygen species (ROS) in the mitochondria, while targeted inhibition of iron overload and ROS accumulation within mitochondria effectively inhibited ferroptosis in cardiomyocytes. Importantly, isoproterenol administration markedly induced ferroptosis in the myocardium in vivo, associated with elevated non-heme iron accumulation driven by HO-1 upregulation. Strikingly, blockade of ferroptosis with ferrostatin-1 or inhibition of HO-1 activity with zinc protoporphyrin (ZnPP) effectively alleviated cardiac necrosis, pathological remodeling, and heart failure induced by isoproterenol administration. Taken together, our results reveal that catecholamine stimulation primarily induces ferroptotic cell death in cardiomyocyte through GPX4 and Bach1-HO-1 dependent signaling pathways. Targeting ferroptosis may represent a novel therapeutic strategy for catecholamine overload-induced myocardial injury and heart failure.
Topics: Humans; Ferroptosis; Reactive Oxygen Species; Cardiotoxicity; Catecholamines; Isoproterenol; Iron; Heart Failure
PubMed: 37499888
DOI: 10.1016/j.freeradbiomed.2023.07.025 -
Internal Medicine (Tokyo, Japan) Sep 2023
Topics: Humans; Isoproterenol; Arrhythmias, Cardiac; Electrocardiography; Cardiac Pacing, Artificial
PubMed: 36642521
DOI: 10.2169/internalmedicine.1081-22 -
International Journal of Molecular... Jul 2021Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and... (Review)
Review
Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.
Topics: Drug Delivery Systems; Heart Failure; Humans; Isoproterenol; Mitochondria, Heart; Oxidation-Reduction; Xanthophylls
PubMed: 34360729
DOI: 10.3390/ijms22157964 -
Biochemical and Biophysical Research... Jun 2022The β-adrenergic receptor (βAR) is the most essential drug target for overactive bladder and has therapeutic potentials for the treatments of type 2 diabetes and...
The β-adrenergic receptor (βAR) is the most essential drug target for overactive bladder and has therapeutic potentials for the treatments of type 2 diabetes and obesity. Here, we report the cryo-electron microscopy structures of the βAR-G signaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound βAR structures revealed that the extracellular loop 2 changes its conformation depending on the bound agonist and plays an essential role in solabegron binding. Moreover, βAR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why βAR prefers mirabegron and solabegron, as the narrow exosite is suitable for binding with agonists with elongated shapes. Our study deepens the understanding of the binding characteristics of βAR agonists and may pave the way for developing βAR-selective drugs.
Topics: Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Benzoates; Biphenyl Compounds; Cryoelectron Microscopy; Diabetes Mellitus, Type 2; Humans; Isoproterenol; Receptors, Adrenergic, beta-3
PubMed: 35489202
DOI: 10.1016/j.bbrc.2022.04.065 -
Biological Psychiatry. Cognitive... Jul 2023Anorexia nervosa (AN) is characterized by low body weight, disturbed eating, body image disturbance, anxiety, and interoceptive dysfunction. However, the neural...
BACKGROUND
Anorexia nervosa (AN) is characterized by low body weight, disturbed eating, body image disturbance, anxiety, and interoceptive dysfunction. However, the neural processes underlying these dysfunctions in AN are unclear. This investigation combined an interoceptive pharmacological probe, the peripheral β-adrenergic agonist isoproterenol, with resting-state functional magnetic resonance imaging to examine whether individuals with AN relative to healthy comparison participants show dysregulated neural coupling in central autonomic network brain regions.
METHODS
Resting-state functional magnetic resonance imaging was performed in 23 weight-restored female participants with AN and 23 age- and body mass index-matched healthy comparison participants before and after receiving isoproterenol infusions. Whole-brain functional connectivity (FC) changes were examined using central autonomic network seeds in the amygdala, anterior insular cortex, posterior cingulate cortex, and ventromedial prefrontal cortex after performing physiological noise correction procedures.
RESULTS
Relative to healthy comparison participants, adrenergic stimulation caused widespread FC reductions in the AN group between central autonomic network regions and motor, premotor, frontal, parietal, and visual brain regions. Across both groups, these FC changes were inversely associated with trait anxiety (State-Trait Anxiety Inventory-Trait), trait depression (9-item Patient Health Questionnaire), and negative body image perception (Body Shape Questionnaire) measures, but not with changes in resting heart rate. These results were not accounted for by baseline group FC differences.
CONCLUSIONS
Weight-restored females with AN show a widespread state-dependent disruption of signaling between central autonomic, frontoparietal, and sensorimotor brain networks that facilitate interoceptive representation and visceromotor regulation. Additionally, trait associations between central autonomic network regions and these other brain networks suggest that dysfunctional processing of interoceptive signaling may contribute to affective and body image disturbance in AN.
Topics: Humans; Female; Isoproterenol; Adrenergic Agents; Anorexia Nervosa; Brain; Amygdala
PubMed: 37055325
DOI: 10.1016/j.bpsc.2022.12.009 -
Anaesthesia Mar 1992
Topics: Glucagon; Humans; Isoproterenol; Propranolol
PubMed: 1567014
DOI: 10.1111/j.1365-2044.1992.tb02157.x -
International Journal of Molecular... Feb 2023CXCR4 is a seven‑transmembrane‑spanning Gi‑coupled receptor for the SDF‑1 chemokine and plays a critical role in cardiovascular development and post‑injury...
CXCR4 is a seven‑transmembrane‑spanning Gi‑coupled receptor for the SDF‑1 chemokine and plays a critical role in cardiovascular development and post‑injury repair. However, the specific role of CXCR4 in cardiomyocytes is incompletely understood. It was hypothesized that CXCR4 activation in cardiomyocytes antagonizes β‑adrenoceptor/Gs signaling‑induced cardiac dysfunction. Cardiomyocyte‑specific CXCR4 knockout (CXCR4‑KO) mice were generated by crossing CXCR4 and MHC‑Cre mice. Their cardiac structure and function in the basal state are equivalent to that of the control MHC‑Cre littermates until at least 4 months old. However, following continuous subcutaneous administration of isoproterenol (Iso) via an osmotic mini‑pump, the ventricular myocardial contractility, dilation, cardiomyocyte apoptosis, and interstitial fibrosis are worse in CXCR4‑KO mice than in MHC‑Cre littermates. In the cultured H9C2 cardiomyocytes, SDF‑1 treatment markedly attenuated Iso‑induced apoptosis and reduction in phospho‑Akt, and this protective effect was lost by knockdown of CXCR4 or by co‑treatment with Gi inhibitors. In conclusion, CXCR4 promotes cardiomyocyte survival and heart function during β‑adrenergic stress.
Topics: Mice; Animals; Myocytes, Cardiac; Isoproterenol; Heart Failure; Cell Death; Myocardium; Apoptosis; Mice, Knockout; Ventricular Remodeling
PubMed: 36579657
DOI: 10.3892/ijmm.2022.5216 -
Comparative Medicine Aug 2009The objective of this study was to determine whether a simple, noninvasive method involving administration of isoproterenol could be used to produce myocardial injury...
The objective of this study was to determine whether a simple, noninvasive method involving administration of isoproterenol could be used to produce myocardial injury and cardiac dysfunction in the mouse heart with a low incidence of mortality. Adult Swiss-Webster mice were injected with isoproterenol (100 mg/kg SC) once daily for 5 d. Myocardial histology and left ventricular (LV) function were assessed 10 to 14 d after the last isoproterenol injection in 14 surviving isoproterenol-treated mice and 15 saline-treated control mice. Left ventricular systolic and diastolic pressures were evaluated in vitro by means of isovolumically contracting, perfused Langendorff preparations. Isoproterenol induced marked endocardial injury, associated with hypertrophy of surviving myocytes, and an increase in myocardial fibrosis (collagen types I and III according to picrosirius red microscopy). The hearts from isoproterenol-treated mice demonstrated decreased LV compliance, as evidenced by an upward shift in the diastolic pressure-volume relationship, with normal LV systolic function. Isoproterenol administration provides a simple, noninvasive means to induce endocardial injury and diastolic dysfunction without significant impairment of systolic function. This model has a low incidence of mortality and may be useful to assess the effects of gene or stem cell therapy on cardiac dysfunction without the potential confounding effects of invasive procedures.
Topics: Adrenergic beta-Agonists; Animals; Heart Injuries; Isoproterenol; Male; Mice
PubMed: 19712573
DOI: No ID Found -
Annual Review of Pharmacology and... Jan 2017Ligand-induced activation of G protein-coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently... (Review)
Review
Ligand-induced activation of G protein-coupled receptors (GPCRs) is a key mechanism permitting communication between cells and organs. Enormous progress has recently elucidated the structural and dynamic features of GPCR transmembrane signaling. Nanobodies, the recombinant antigen-binding fragments of camelid heavy-chain-only antibodies, have emerged as important research tools to lock GPCRs in particular conformational states. Active-state stabilizing nanobodies have elucidated several agonist-bound structures of hormone-activated GPCRs and have provided insight into the dynamic character of receptors. Nanobodies have also been used to stabilize transient GPCR transmembrane signaling complexes, yielding the first structural insights into GPCR signal transduction across the cellular membrane. Beyond their in vitro uses, nanobodies have served as conformational biosensors in living systems and have provided novel ways to modulate GPCR function. Here, we highlight several examples of how nanobodies have enabled the study of GPCR function and give insights into potential future uses of these important tools.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Isoproterenol; Ligands; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Single-Domain Antibodies
PubMed: 27959623
DOI: 10.1146/annurev-pharmtox-010716-104710 -
Physiological Reports Jan 2022Current understanding of ventricular action potential adaptation to physiological stress is generally based on protocols using non-physiological rates and conditions...
PURPOSE
Current understanding of ventricular action potential adaptation to physiological stress is generally based on protocols using non-physiological rates and conditions isolating rate effects from escalating adrenergic stimulation. To permit refined understanding, ventricular action potentials were assessed across physiological pacing frequencies in the presence and absence of adrenergic stimuli. Isolated and combined effects were analyzed to assess their ability to replicate in-vivo responses.
METHODS
Steady-state action potentials from ventricular myocytes isolated from male Wistar rats (3 months; N = 8 animals) were recorded at 37°C with steady-state pacing at 1, 2, 4, 6, 8 and 10 Hz using whole-cell patch-clamp. Action potential repolarization to 25, 50, 75, 90 and 100% of full repolarization (APD ) was compared before and after 5 nM, 100 nM and 1 µM isoproterenol doses.
RESULTS
A Repeated measures ANOVA found APD shortened with 5 nM isoproterenol infusion by 6-25% (but comparable across doses) (p ≤ 0.03). Pacing frequencies emulating a normal rat heart rate (6 Hz) prolonged APD 23% compared with 1 Hz pacing. Frequencies emulating exercise or stress (10 Hz) shortened APD (29%).
CONCLUSION
These results demonstrate modest action potential shortening in response to adrenergic stimulation and elevations in pacing beyond physiological resting rates. Our findings indicate changes in action potential plateau and late repolarization predominantly underlie simulated exercise responses in the rat heart. This work provides novel action potential reference data and will help model cardiac responses to physiological stimuli in the rat heart via computational techniques.
Topics: Action Potentials; Animals; Heart Ventricles; Isoproterenol; Male; Myocytes, Cardiac; Rats; Rats, Wistar
PubMed: 35076184
DOI: 10.14814/phy2.15166