A5071599807- Receptor Mechanisms and Signaling
- Renin-Angiotensin System Studies
- Computational Drug Discovery Methods
- Neuropeptides and Animal Physiology
- Aortic aneurysm repair treatments
- Protein Structure and Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Monoclonal and Polyclonal Antibodies Research
- Cardiac electrophysiology and arrhythmias
- Pharmacogenetics and Drug Metabolism
- Magnesium Alloys: Properties and Applications
- Biomedical Research and Pathophysiology
- Mitochondrial Function and Pathology
- Connective Tissue Growth Factor Research
- Genomics and Chromatin Dynamics
- Mechanisms of cancer metastasis
- Mass Spectrometry Techniques and Applications
- Pulmonary Hypertension Research and Treatments
- Neurobiology and Insect Physiology Research
- Circular RNAs in diseases
- Retinal Development and Disorders
- Protein Degradation and Inhibitors
- Plant Micronutrient Interactions and Effects
- Lipoproteins and Cardiovascular Health
- Cytokine Signaling Pathways and Interactions
Cleveland Clinic
1997-2025
Cleveland Clinic Lerner College of Medicine
2009-2022
Case Western Reserve University
1998-2021
Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti-hypertensive drugs and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies toward cardiovascular etiologies. The structural basis for modulation by different peptide non-peptide ligands has remained elusive. Here, we report crystal structure of human complex with an inverse agonist...
Cardiac hypertrophy is a risk factor independent of blood pressure; however, the mechanisms that distinguish pathological remodelling due to local cues from pressure overload are unresolved. This study was aimed at discovering novel gene expression mechanism in heart failure. In angiotensin II type 1 receptor (AT1R) transgenic mice (TG), we found significant increase mRNA and total STAT3 (T-STAT3) protein, but not phosphorylated residues Y705 S727. A net nuclear accumulation this...
MAS is a G protein-coupled receptor (GPCR) implicated in multiple physiological processes. Several peptide ligands such as angiotensin-(1–7), angiotensin fragments and neuropeptide FF (NPFF) are reported to act on MAS. Studies of conventional protein signaling desensitization upon stimulation with the limited so far. Therefore, we systematically analyzed signals activated by ligands. MAS-selective non-peptide that were previously shown activate proteins used controls for comparison common...
Abstract BACKGROUND Plasma accumulation of the gut microbial metabolite, 4-ethylphenylsulfate (4EPS), produced from dietary protein aromatic amino acids has been observed in correlative and associative studies cardiovascular, renal, metabolic neurological diseases. 4EPS level increases upon AngII infusion mice. How alters host physiology to contribute progression any disease state is currently unknown. METHODS To test hypothesis that interferes with angiotensin binding AT1R, we used multiple...
Aortic aneurysm (AA) is a "silent killer" human disease with no effective treatment. Although the therapeutic potential of various pharmacological agents have been evaluated, there are reports β-arrestin-biased AT1R (angiotensin-II type-1 receptor) agonist (TRV027) used to prevent progression AA.
We present a succession of structural changes involved in hormone peptide activation prototypical GPCR. Microsecond molecular dynamics simulation generated conformational ensembles reveal propagation through key "microswitches" within human AT1R bound to native hormone. The endocrine octa-peptide angiotensin II (AngII) activates signaling our bodies which maintains physiological blood pressure, electrolyte balance, and cardiovascular homeostasis. Excessive is associated with pathogenesis...
Significance High-resolution structural knowledge is a key driver for discovering small molecules to target functional motifs in G protein-coupled receptors (GPCRs). Reports of autoantibodies targeting extracellular GPCRs are increasing with no therapies sight. We address this void using the autoantibody epitope AT1R as discover molecule inhibitors antibody. Resulting also exerted allosteric effects on agonist signaling. This useful consideration inhibitor development other which cryptic...
Heterotrimeric G-protein signal transduction initiated by G-protein-coupled receptors (GPCRs) in the plasma membrane is thought to propagate through protein-protein interactions of subunits, Gα and Gβγ cytosol. In this study, we show novel nuclear functions demonstrating interaction Gβ2 with integral components chromatin effects depletion on global gene expression. Agonist activation several GPCRs including angiotensin II type 1 receptor specifically augmented levels nucleus interacted...
Crystal structures of the human angiotensin II type 1 receptor (AT1R) complex with antihypertensive agent ZD7155 (PDB id: 4YAY) and blood pressure medication Benicar 4ZUD) showed that binding poses both antagonists are similar. This finding implies clinically used blocking (ARB) drugs may interact in a similar fashion. However, observed differences pharmacological therapeutic efficacies ARBs lead to question whether dynamic interactions AT1R vary. To address this, we performed induced-fit...
Chronic activation of angiotensin II (AngII) type 1 receptor (AT(1)R), a prototypical G protein-coupled (GPCR) induces gene regulatory stress which is responsible for phenotypic modulation target cells. The AT(1)R-selective drugs reverse the in various cardiovascular diseases. However, molecular mechanisms are not clear. We speculate that states AT(1)R modify composition histone isoforms and post-translational modifications (PTM), thereby alter structure-function dynamics chromatin. combined...
We tested the hypothesis that in intact heart, mitochondrial metabolism is activated by Ca2+ uptake during increased work. measured left ventricular pressure (LVP), pyruvate dehydrogenase (PDH) activity, and A band elemental content electron probe microanalysis (EPMA) Langendorff-perfused hamster hearts under control conditions, after isoproterenol (10(-6) M) stimulation, increasing perfusion from 60 to 100 mmHg. Hearts were rapidly frozen, then EPMA was performed on cryosections cut surface...
Perspectives on whether the functions of MAS, a G protein-coupled receptor, are beneficial or deleterious in heart remain controversial. MAS gene knockout reduces coronary vasodilatation leading to ischemic injury. protein signaling activated by has been implicated progression adaptive cardiac hypertrophy failure and fibrosis. In present study, we observed increased expression connective tissue growth factor (CTGF) collagen genes failing (HF) human samples when compared non-failing (NF)....
The discovery of beta-arrestin-related approximately 46-kDa polypeptide in transfected cells and mouse hearts led us to examine angiotensin II type 1 receptor (AT(1)R)-dependent proteolytic cleavage beta-arrestin(s). Receptor-ligand induced proteolysis beta-arrestin(s) is novel, especially the endocrine system, since and/or splice variants nonvisual arrestins are unknown. We used a strategy retrieve AT(1)R-engaged isoforms beta-arrestin confirm direct interaction fragments with this G...
An increase in extracellular adenosine triphosphate (ATP) is arrhythmogenic rat cardiac myocytes and ATP levels are elevated during ischemia. To gain insight into the mechanism by which arrhythmic contractions generated, we investigated changes subcellular elemental content electron probe microanalysis (EPMA) isolated adult stimulated analog, 2-methylthio-ATP (2-M-S-ATP). We also measured effects of 2-M-S-ATP stimulation on myocyte cell shortening. In electrically myocytes, generated...
Background: The clinical data suggest an association of autoantibodies (AAb) targeting angiotensin II type1 receptor (AT1R) and outcomes in heart failure (HF) preeclampsia. Notably, patient’s risk increases 2 to 4-fold for diseases hypertension. Although AT1R blockers (ARBs) have emerged as a key component the therapeutic arsenal against CVD, we believe that rather than completely blocking signaling, maintaining balanced signaling is crucial cardiovascular homeostasis. Therefore, posit...
Background: Regulator of G protein signaling proteins (RGS) are known to regulate coupled receptor (GPCR) at the plasma membrane through their GTPase-activating activity. We have previously identified RGS2 as a downstream target unphosphorylated Signal Transducer and Activator Transcription 3 (U-STAT3). U-STAT3 mediated Angiotensin II (AngII) type 1 (AT1R), GPCR, induced cardiac hypertrophy but mechanism is unclear. Hypothesis: mediator regulated Ang II/AT1R signaling. Methods Results: In...