Abstract P336: Endogenous Alpha-1a Adrenergic Receptors Promote Cardiomyocyte Survival Through Suppression Of Rip Kinase-mediated Necroptosis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Jiandong Zhang ◽  
Peyton Sandroni ◽  
Wei Huang ◽  
Brian C Jensen
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Caspase 3 ◽  
Underlying Mechanism ◽  
Hmgb1 Level ◽  
Programmed Necrosis ◽  
Apoptosis Markers ◽  
Kinase Pathway ◽  
Cardiomyocyte Survival ◽  
Serum Hmgb1 Level

Our previous work has demonstrated essential protective roles for the endogenous cardiomyocyte alpha-1A adrenergic receptor (α1A-AR) subtype in mouse models of heart failure. However, the underlying mechanism of this protective phenotype is unclear. To address this gap in knowledge, we bred a mouse line lacking α1A-ARs on cardiomyocytes by crossing αMHC-cre mice with floxed α1A mice (CMKO= cre+ fl/fl, CMWT= cre- fl/fl), and subjected males to permanent LAD ligation. CMKO mice had increased serum HMGB1 level, larger infarcts and higher mortality. We found that RIP1/3-mediated programmed necrosis (necroptosis), but not apoptosis was exaggerated in CMKO mice 3 days after ligation. We then tested whether RIP1 inhibition with Nec-1s could mitigate this injury. Mice were given Nec-1s (1.65 mg/kg) or vehicle 10 mins prior to LAD ligation, followed by daily IV injection. Nec-1s treatment diminished post-ligation RIP1 (0.62±0.02 vs. 0.78±0.23 A.U., p=NS) and RIP3 expression (0.33±0.1 vs. 0.26±0.10 A.U., p=NS) in CMWT and CMKO mice respectively. Serum level of HMGB1 on D3 was markedly reduced in both CMWT (45.1%) and CMKO (61.1 %) after Nec-1s treatment. There was no difference between Nec-1s treated CMWT and CMKO mice (147±53 vs. 174±37 pg/mL, p=NS), indicating that blocking the RIP kinase pathway abrogates the exaggerated cell death in CMKO mice after ligation. Likewise, Nec-1s-treated CMKO mice had similar infarct areas to CMWT controls (16.2±4.5 vs. 19.9±4.6%, p=NS), further confirming that targeting necroptosis abrogates pathological damage. Collectively these Nec-1s data suggest that RIP-mediated necroptosis may account for larger infarcts in CMKO mice. Interestingly, expression of the apoptosis markers c-caspase-3 and PARP was similar between CMWT and CMKO mice, suggesting that the α1A-AR specifically regulates necroptosis. In sum, our data demonstrate that RIP kinase-mediated necroptosis contributes to susceptibility to injury in mice lacking cardiomyocyte α1A-ARs.

scholarly journals Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomonori Hara ◽  
Manabu Toyoshima ◽  
Yasuko Hisano ◽  
Shabeesh Balan ◽  
Yoshimi Iwayama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Caspase 3 ◽  
Intervention Strategy ◽  
Underlying Mechanism ◽  
Carbonyl Stress ◽  
Gene Encoding ◽  
Induced Pluripotent

AbstractCarbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.

Inhibition of Glutamatergic Synaptic Input to Spinal Lamina IIo Neurons by Presynaptic α2-Adrenergic Receptors

2002 ◽  
Vol 87 (4) ◽  
pp. 1938-1947 ◽  
Author(s):  
Yu-Zhen Pan ◽  
De-Pei Li ◽  
Hui-Lin Pan
Keyword(s):  
Receptor Antagonist ◽  
Synaptic Input ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Dorsal Root ◽  
Primary Afferents ◽  
Noradrenergic System ◽  
Analgesic Action ◽  
Adrenergic Agonists ◽  
Excitatory Synaptic Input

Activation of spinal α2-adrenergic receptors by the descending noradrenergic system and α2-adrenergic agonists produces analgesia. However, the sites and mechanisms of the analgesic action of spinally administered α2-adrenergic receptor agonists such as clonidine are not fully known. The dorsal horn neurons in the outer zone of lamina II (lamina IIo) are important for processing nociceptive information from C-fiber primary afferents. In the present study, we tested a hypothesis that activation of presynaptic α2-adrenergic receptors by clonidine inhibits the excitatory synaptic input to lamina IIo neurons. Whole cell voltage-clamp recordings were performed on visualized lamina IIo neurons in the spinal cord slice of rats. The miniature excitatory postsynaptic currents (mEPSCs) were recorded in the presence of tetrodotoxin, bicuculline, and strychnine. The evoked EPSCs were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Both mEPSCs and evoked EPSCs were abolished by application of 6-cyano-7-nitroquinoxaline-2,3-dione. Clonidine (10 μM) significantly decreased the frequency of mEPSCs from 5.8 ± 0.9 to 2.7 ± 0.6 Hz (means ± SE) without altering the amplitude and the decay time constant of mEPSCs in 25 of 27 lamina IIo neurons. Yohimbine (2 μM, an α2-adrenergic receptor antagonist), but not prazosin (2 μM, an α1-adrenergic receptor antagonist), blocked the inhibitory effect of clonidine on the mEPSCs. Clonidine (1–20 μM, n = 8) also significantly attenuated the peak amplitude of evoked EPSCs in a concentration-dependent manner. The effect of clonidine on evoked EPSCs was abolished in the presence of yohimbine ( n = 5). These data suggest that clonidine inhibits the excitatory synaptic input to lamina IIo neurons through activation of α2-adrenergic receptors located on the glutamatergic afferent terminals. Presynaptic inhibition of glutamate release from primary afferents onto lamina IIoneurons likely plays an important role in the analgesic action produced by activation of the descending noradrenergic system and α2-adrenergic agonists.

scholarly journals Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Barbara Jana ◽  
Jarosław Całka
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Domestic Animals ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Beta Adrenergic Receptor ◽  
Pharmacological Modulation ◽  
Uterine Inflammation ◽  
Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

scholarly journals Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors.

1993 ◽  
Vol 268 (5) ◽  
pp. 3201-3208
Author(s):  
S. Pippig ◽  
S. Andexinger ◽  
K. Daniel ◽  
M. Puzicha ◽  
M.G. Caron ◽  
...  
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
Beta 2

α-Adrenergic receptor modulation of the intrathoracic efferent sympathetic nervous system regulating the canine heart

1989 ◽  
Vol 67 (10) ◽  
pp. 1199-1204 ◽  
Author(s):  
J. A. Armour
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Blocking Agent ◽  
Sympathetic Ganglia ◽  
Canine Heart ◽  
Receptor Modulation ◽  
Adrenergic Antagonist ◽  
Cervical Ganglia ◽  
Β Adrenergic Receptors ◽  
Stimulation Of

The augmentation of ventricular inotropism induced by electrical stimulation of acutely decentralized efferent sympathetic preganglionic axons was reduced, but still present, following administraiton of hexamethonium (10 mg/kg i.v.). While hexamethonium continued to be administered, the cardiac augmentations so induced were enhanced significantly following administration of the α-adrenergic receptor blocking agent, phentolamine myselate (1 mg/kg i.v.). Stimulation of the sympathetic efferent postganglionic axons in cardiopulmonary nerves induced cardiac augmentations that were unchanged following administration of these agents singly or together. The cardiac augmentations induced by stimulation of efferent preganglionic sympathetic axons were unchanged when phentolamine was administered alone. The augmentations of cardiac inotropism induced by efferent postganglionic sympathetic axonal stimulation were decreased following local administration of the β-adrenergic antagonist timolol into the ipsilateral stellate and middle cervical ganglia. Thereafter, these augmentations were unchanged following the subsequent intravenous administration of phentolamine. It is concluded that the activation of cardiac neurons in the stellate and middle cervical ganglia by stimulation of efferent preganglionic sympathetic axons can be modified by α-adrenergic receptors and that these effects are dependent upon β-adrenergic receptors, not nicotinic ones, in intrathoracic ganglia.Key words: α-adrenergic inotropism, sympathetic ganglia, hexamethonium, phentolamine.

Estimation of the genetic activity of epinephrine hydrotartrate on the model of erythrocytes in peripheral blood in mice

2021 ◽  
Vol 1 (2) ◽  
pp. 6-10
Author(s):  
M. Ya. Ibragimova ◽  
◽  
S. Yu. Zaytsev ◽  
V. V. Semenov ◽  
◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Genetic Effects ◽  
Receptor Ligand ◽  
Antimutagenic Effect ◽  
Genetic Activity ◽  
Ad Libitum ◽  
And Control ◽  
Β Adrenergic Receptors

The aim of the study was to evaluate the genetic activity of erythrocytes in peripheral on the model of peripheral blood erythrocytes in mice. The studies were carried out on mice (males) of the C 57B4/6 line weighing 20 g (1,5–2 months of age). For each experimental and control variant, six males were taken. The animals were kept in vivarium conditions according to international criteria for rinofix bedding, food and water ad libitum. When determining the genetic effects, the adrenergic receptor ligand was injected subcutaneously once. After 8 hours, a mutation inducer, an alkylating drug, cyclophosphamide, was injected intraperitoneally at a dose of 30 mg/kg. Before the end of the experiment in 2,5 hour, mice were injected intraperitoneally with 2.5 mg/kg of colchicine. 24 hours after injection, the animals were euthanized by delongation. The number of erythrocytes with micronuclei was counted from 2000 analyzed cells. The greatest antimutagenic effect (87,5%) of epinephrine hydrotartrate, a stimulator of α- and β-adrenergic receptors, was found at doses of 5 and 0,5 mg/kg.

Abstract O-3: A β1-Adrenergic Receptor/β-Arrestin1-Regulatable MicroRNA, MiR-150 Protects the Mouse Heart from Ischemic Injury by Repressing Pro-apoptotic Egr2 and P2x7r

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Il-man Kim ◽  
Yaoping Tang ◽  
Yongchao Wang ◽  
Kyoung-mi Park ◽  
Qiuping Hu
Keyword(s):  
Adrenergic Receptor ◽  
Cardiac Injury ◽  
Ischemic Injury ◽  
Mouse Heart ◽  
Functional Remodeling ◽  
Β Blocker ◽  
Genetic Deletion ◽  
Circulating Levels ◽  
Cardiomyocyte Survival

MicroRNA (miR)-150 is down-regulated in patients with acute myocardial infarction (AMI), atrial fibrillation, dilated and ischemic cardiomyopathy as well as in various mouse heart failure (HF) models. Circulating miR-150 has been recently proposed as a better biomarker of HF than clinically used markers such as brain natriuretic peptide. We recently showed that β-arrestin1-biased β1-adrenergic receptor (β1AR) cardioprotective signaling activated by the β-arrestin-biased β-blocker, carvedilol (Carv) stimulates the processing of miR-150 in the heart (see figure A). However, the potential role of miR-150 in ischemic injury and HF is unknown. Here, we show that genetic deletion of miR-150 in mice causes abnormalities in cardiac structural and functional remodeling after MI. The cardioprotective roles of miR-150 during ischemic injury were attributed to repression of the pro-apoptotic genes egr2 (zinc binding transcription factor induced by ischemia) and p2x7r (pro-inflammatory ATP receptor) [see figure B]. These findings reveal a pivotal role for miR-150 as a regulator of cardiomyocyte survival during cardiac injury. In conclusion, our study will help to stratify HF patients that may respond better to β-arrestin-biased β-blockers, which is guided by circulating levels of miR-150.

scholarly journals Bitransgenesis with β2-Adrenergic Receptors or Adenylyl Cyclase Fails to Improve β1-Adrenergic Receptor Cardiomyopathy

2008 ◽  
Vol 1 (3) ◽  
pp. 221-227 ◽  
Author(s):  
Natalia Petrashevskaya ◽  
Brigitte R. Gaume ◽  
Kathryn A. Mihlbachler ◽  
Gerald W. Dorn II ◽  
Stephen B. Liggett
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor

Quantitative study of α-adrenergic receptors in circular and longitudinal muscle of isthmus of rabbit fallopian tube and in rabbit aorta

1977 ◽  
Vol 55 (5) ◽  
pp. 1102-1106
Author(s):  
K. Rajkumar ◽  
P. L. Sharma
Keyword(s):  
Fallopian Tube ◽  
Quantitative Study ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Longitudinal Muscle ◽  
Circular Muscle ◽  
Rabbit Aorta ◽  
Practical Application ◽  
Human Fallopian Tube ◽  
Receptor Agonists And Antagonists

The affinity of phenylephrine (pD2 value) and KB value for phentolamine for the α-adrenergic receptors of circular and longitudinal muscle of isthmus of rabbit fallopian tube and rabbit aorta have been estimated. The affinity of both phenylephrine and phentolamine was significantly more for the α adrenoceptors of the longitudinal muscle of isthmus of rabbit fallopian tube and rabbit aorta than circular muscle of isthmus of fallopian tube.The results of this investigation suggest that α adrenoceptors of circular muscle of isthmus are atypical. If this holds good for the human fallopian tube, the development of selective α-adrenergic-receptor agonists and antagonists may be of potential practical application for the control of fertility.

Sign in / Sign up

Export Citation Format

Share Document