Abstract 56: Candesartan And Valsartan, Contrary To Irbesartan, Are Potent Biased Antagonists Of Adrenal (beta)arrestin-dependent, Angiotensin II Type 1 Receptor-induced Aldosterone Production And Improve Cardiac Function Post-myocardial Infarction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Anastasios Lymperopoulos ◽  
Karlee Walklett ◽  
Samalia Dabul ◽  
Ashley Siryk ◽  
Emmanuel Sturchler ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
G Protein ◽  
Plasma Aldosterone ◽  
Post Myocardial Infarction ◽  
Aldosterone Production

Introduction: The scaffolding protein βarrestin1 (βarr1) by the angiotensin II (AngII) type 1 receptor (AT 1 R) mediates AngII-induced aldosterone production in vitro and physiologically in vivo, thereby exacerbating heart failure (HF) progression post-myocardial infarction (MI). Herein, we sought to investigate the relative potency of various AT 1 R antagonist drugs (sartans) at inhibiting βarr vs. G protein activation and hence aldosterone production in vitro and in vivo. We also investigated the alterations in plasma aldosterone levels conferred by these agents and their impact on cardiac function of post-MI rats. Methods: For the in vitro tests, transfected CHO and adrenocortical H295R cells were used. For in vivo studies, post-MI rats overexpressing βarr1 in their adrenals received 7-day-long treatments with the drugs of interest. Results: Among the sartans tested, candesartan and valsartan were the most potent βarr activation and βarr-mediated aldosterone production inhibitors in vitro, as well as the most “biased” antagonists towards βarr vs. G-protein inhibition. Conversely, losartan and irbesartan were the least potent βarr inhibitors and the least “biased” antagonists towards βarr inhibition. These in vitro findings were corroborated in vivo, since candesartan and valsartan, contrary to irbesartan, caused significant plasma aldosterone reductions in post-MI rats. Accordingly, cardiac ejection fraction (EF) and contractility were significantly augmented in candesartan- and valsartan-treated rats (EF: 41.1±1% and 40±1% respectively, vs. 35±0.3% for saline-treated), but further deteriorated in irbesartan-treated post-MI rats (EF: 32±1%, n=7 rats/group). Conclusions: These findings provide important insights that might aid pharmacotherapeutic decisions (i.e. individual agent selections) involving this commonly prescribed cardiovascular drug class (sartans).

scholarly journals GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

2020 ◽  
Vol 21 (2) ◽  
pp. 574
Author(s):  
Celina M. Pollard ◽  
Jennifer Ghandour ◽  
Natalie Cora ◽  
Arianna Perez ◽  
Barbara M. Parker ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Adrenal Cortex ◽  
Zona Glomerulosa ◽  
Type I ◽  
Signaling Crosstalk ◽  
Aldosterone Production ◽  
Steroidogenic Acute Regulatory

Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone via both G proteins and the adapter protein βarrestin1, which binds the receptor following its phosphorylation by GPCR-kinases (GRKs) to initiate G protein-independent signaling. β-adrenergic receptors (ARs) also induce aldosterone production in AZG cells. Herein, we investigated whether GRK2 or GRK5, the two major adrenal GRKs, is involved in the catecholaminergic regulation of AngII-dependent aldosterone production. In human AZG (H295R) cells in vitro, the βAR agonist isoproterenol significantly augmented both AngII-dependent aldosterone secretion and synthesis, as measured by the steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA inductions. Importantly, GRK2, but not GRK5, was indispensable for the βAR-mediated enhancement of aldosterone in response to AngII. Specifically, GRK2 inhibition with Cmpd101 abolished isoproterenol’s effects on AngII-induced aldosterone synthesis/secretion, whereas the GRK5 knockout via CRISPR/Cas9 had no effect. It is worth noting that these findings were confirmed in vivo, since rats overexpressing GRK2, but not GRK5, in their adrenals had elevated circulating aldosterone levels compared to the control animals. However, treatment with the β-blocker propranolol prevented hyperaldosteronism in the adrenal GRK2-overexpressing rats. In conclusion, GRK2 mediates a βAR-AT1R signaling crosstalk in the adrenal cortex leading to elevated aldosterone production. This suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems at the level of the adrenal cortex and that its inhibition might be therapeutically advantageous in hyperaldosteronism-related conditions.

Abstract 295: Enhanced Cardiac Function And Lower Circulating Aldosterone Levels In βArrestin1 Knockout Mice During Post-myocardial Infarction Heart Failure Progression

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Anastasios Lymperopoulos ◽  
Giuseppe Rengo ◽  
Erhe Gao ◽  
Ashley Siryk ◽  
Samalia Dabul ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Underlying Mechanism ◽  
Post Myocardial Infarction ◽  
Aldosterone Production ◽  
Heart Failure Progression ◽  
Adverse Remodeling ◽  
And Function

Introduction: Chronic heart failure (HF) is characterized by enhanced circulating cardiotoxic hormones, among the most prominent of which is aldosterone, which contributes to the increased morbidity and mortality of the disease by promoting cardiac adverse remodeling post-myocardial infarction (MI). Cardiac β-adrenergic receptor (ΑR) desensitization and downregulation are a hallmark abnormality in HF at the molecular level and are due to the concerted action of cardiac G protein-coupled receptor kinase-2 (GRK2), together with its co-factors in receptor desensitization, the βarrestins (βarrs). We have also recently established that βarr1 promotes angiotensin II-dependent aldosterone production in the adrenal cortex, and this leads to elevated circulating aldosterone levels in vivo, both under normal conditions and during post-MI HF progression. Hypothesis: Herein, we sought to investigate the effects of genetically deleting βarr1 on post-MI cardiac function and hyperaldosteronic status in mice progressing to HF. Methods: We uitilized the βarr1KO mouse model and studied these mice at 4 weeks after surgically induced MI, in parallel with C57/B6 wild type (WT) controls. Cardiac function was assessed by echocardiography and in vivo catheterization. Plasma aldosterone was measured by ELISA. Results: Cardiac function is markedly improved in βarr1KO`s at 4 weeks post-MI, as evidenced by increased ejection fraction compared to WT mice (41.5 + 2.8 % vs. 21.8 + 2.4 %, respectively, n=9, p<0.0001) and increased isoproterenol-induced contractility. Additionally, cardiac dimensions are significantly reduced compared to WT`s, indicating attenuation of adverse cardiac remodeling. Importantly, plasma circulating aldosterone levels are significantly lowered and cardiac βAR signaling and function appear elevated in post-MI βarr1KO`s compared to control WT`s. Conclusions: Genetic deletion of βarr1 substantially improves cardiac function, adverse remodeling, hyperaldosteronism, and cardiac βAR function during post-MI HF progression. The underlying mechanism is attenuation of both cardiac βAR desensitization/downregulation and adrenal aldosterone production, which is βarr1-dependent.

RESPONSES OF ALDOSTERONE-PRODUCING ADENOMAS TO ACTH AND ANGIOTENSINS

1979 ◽  
Vol 92 (4) ◽  
pp. 702-709 ◽  
Author(s):  
Takao Saruta ◽  
Tetsuji Okuno ◽  
Toyohisa Eguchi ◽  
Ryuichi Nakamura ◽  
Ikuo Saito ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Control Mechanism ◽  
Normal Subjects ◽  
Diurnal Variations ◽  
Plasma Aldosterone ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma ◽  
Normal Controls

ABSTRACT To elucidate the control mechanism of aldosterone production in primary aldosteronism, in vivo and in vitro studies were done in 7 patients with aldosterone-producing adenomas. In the in vivo study, plasma aldosterone was stimulated more significantly by synthetic ACTH than by angiotensin II or furosemide. Diurnal variations of plasma aldosterone, which were studied in 4 patients, were similar to those seen in normal controls. In agreement with the results in the in vivo study, the in vitro study also revealed ACTH stimulated aldosterone and deoxycorticosterone (DOC) from the adenoma more markedly than angiotensin II or III. There was no adenoma which was more sensitive to angiotensin II or III than to ACTH. From these results it is considered that changes in plasma aldosterone induced by the exogenous administration of angiotensin II or ACTH in patients with aldosterone-producing adenoma are mainly based on changes in aldosterone production in the adenoma. Furthermore, in patients with an aldosterone-producing adenoma in whom diurnal variations of plasma aldosterone similar to those in normal subjects are observed, responses of aldosterone to angiotensin II are supposed to be less than those to ACTH.

scholarly journals Garcinoic Acid Improves Cardiac Function and Enhances Angiogenesis Following Myocardial Infarction

2021 ◽  
Author(s):  
Hongyao Hu ◽  
Wei Li ◽  
Yanzhao Wei ◽  
Hui Zhao ◽  
Zhenzhong Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Ventricular Remodeling ◽  
Vehicle Group ◽  
Potential Mechanism ◽  
Garcinia Kola ◽  
Angiogenic Proteins

Abstract Cardiac ischemia impairs angiogenesis in response to hypoxia, resulting in ventricular remodeling. Garcinoic acid (GA), the extraction from the plant garcinia kola, is validated to attenuate inflammatory response. However, the role of GA in heart failure (HF) and neovascularization after myocardial infarction (MI) is incompletely understood. The present study is striving to explore the role of GA and the potential mechanism of which in cardiac function after MI. SD rats were randomized into sham group, MI+vehicle group, and MI+GA group in vivo. Human umbilical endothelial cells (HUVECs) were cultured in vehicle or GA, and then additionally exposed to 2% hypoxia environment in vitro. MI rats displayed a dramatically reduced myocardial injury, cardiac function and vessel density in the peri-infarcted areas. GA delivery markedly improved cardiac performance and promoted angiogenesis. In addition, GA significantly enhanced tube formation in HUVECs under hypoxia condition. Furthermore, the expressions of pro-angiogenic factors HIF-1α, VEGF-A and bFGF, and pro-angiogenic proteins phospho-VEGFR2Tyr1175 and VEGFR2, as well as phosphorylation levels of Akt and eNOS were increased by GA treatment. In conclusion, GA preserved cardiac function after MI probably via promoting neovascularization. And the potential mechanism may be partially through upregulating the expressions of HIF-1α, VEGF-A, bFGF, phospho-VEGFR2Tyr1175 and VEGFR2 and activating the phosphorylations of Akt and eNOS.

scholarly journals Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1872
Author(s):  
Martha Sahylí Ortega Pijeira ◽  
Paulo Sérgio Gonçalves Nunes ◽  
Sofia Nascimento dos Santos ◽  
Zhengxing Zhang ◽  
Arian Pérez Nario ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Binding Affinity ◽  
Renin Angiotensin System ◽  
Prosthetic Group ◽  
Positron Emission ◽  
One Step ◽  
Group 2

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.

scholarly journals Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling

2015 ◽  
Vol 309 (8) ◽  
pp. C541-C550 ◽  
Author(s):  
Carla P. Carneiro de Morais ◽  
Juliano Z. Polidoro ◽  
Donna L. Ralph ◽  
Thaissa D. Pessoa ◽  
Maria Oliveira-Souza ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
G Protein ◽  
Extracellular Fluid ◽  
The Body ◽  
Type I ◽  
Ang Ii ◽  
Receptor Signaling

Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-dependent intracellular pH recovery. We found that 10−7 M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization.

scholarly journals Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR‐181a in a Rodent Chronic Myocardial Infarction Model

2020 ◽  
Vol 9 (13) ◽  
Author(s):  
Evgeniya Vaskova ◽  
Gentaro Ikeda ◽  
Yuko Tada ◽  
Christine Wahlquist ◽  
Marc Mercola ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Cardiac Function ◽  
Pluripotent Stem Cell ◽  
Myocardial Injury ◽  
Induced Pluripotent Stem Cell ◽  
Injury Model ◽  
Induced Pluripotent

Background Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including mi RNA s, mRNA s, lnc RNA s, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. Methods and Results We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human‐induced pluripotent stem cell‐derived cardiomyocytes under normoxic and hypoxic injury model in vitro , and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell‐derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next‐generation sequencing of these exosomes exhibited downregulation of the expression of rno‐miR‐181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR‐181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR‐181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. Conclusions We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the mi RNA expression level in the exosome payload.

scholarly journals High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction

2017 ◽  
Vol 312 (5) ◽  
pp. H1002-H1012 ◽  
Author(s):  
Junyu Yang ◽  
Milton E. Brown ◽  
Hanshuo Zhang ◽  
Mario Martinez ◽  
Zhihua Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Nadph Oxidase ◽  
Cardiac Function ◽  
High Throughput ◽  
High Throughput Screening ◽  
Heart Function ◽  
In Vivo Studies ◽  
Screening System

Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases. NEW & NOTEWORTHY NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening to identify microRNAs that target Nox2 and improve cardiac function after infarction.

scholarly journals Chamber Specification During Direct Cardiac Reprogramming

2021 ◽  
Author(s):  
Zhentao Zhang ◽  
Jesse Villalpando ◽  
Wenhui Zhang ◽  
Young-Jae Nam
Keyword(s):  
Myocardial Infarction ◽  
Transcription Factors ◽  
Post Myocardial Infarction ◽  
Heart Regeneration ◽  
Proof Of Concept ◽  
Major Fraction ◽  
Regenerative Approach ◽  
Inherent Advantage

Abstract Forced expression of core cardiogenic transcription factors can directly reprogram fibroblasts to induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. This cardiac reprogramming approach provides a proof of concept for induced heart regeneration by converting a fibroblast fate to a cardiomyocyte fate. However, it remains elusive whether chamber-specific cardiomyocytes can be generated by cardiac reprogramming. Therefore, we assessed the ability of the cardiac reprogramming approach for chamber specification in vitro and in vivo. We found that in vivo cardiac reprogramming post-myocardial infarction exclusively generates ventricular-like iCMs, while a major fraction of iCMs generated in vitro fail to determine their chamber identities. Our results indicate that in vivo cardiac reprogramming may have an inherent advantage of generating chamber-matched new cardiomyocytes as a potential heart regenerative approach.

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