FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1972506323> ?p ?o ?g. }

• W1972506323 endingPage "959" @default.
• W1972506323 startingPage "956" @default.
• W1972506323 abstract "COMPLEX biochemical, pharmacologic, and physiologic changes occur with advancing age in the myocardium. These changes may be subtle and virtually undetectable under resting steady state conditions, but become prominent under stressful stimulation. In this issue of Anesthesiology, Birenbaum et al. 1provide evidence for impaired inotropic response (approximately 30%) to β-adrenergic stimulation in aged versus young rat hearts. Apart from β1-adreneric receptor (AR) down-regulation, they further demonstrate that increased formation of nitric oxide deriving from neuronal nitric oxide synthase (nNOS) via the activated β3-AR subtype signaling pathway is responsible for the reduced inotropy in senescent hearts.Since the late 1980s, it is known that three β-AR subtypes, namely the β1-, β2-, and β3-AR, participate in the regulation of cardiovascular function. Expression of β3-ARs in human hearts was first reported in 1996 by Gauthier et al. 2The β3-AR shares only approximately 50% homology with β1/2-ARs and is particular in certain aspects (table 1). First, in contrast to β1/2-ARs (monoexonic genes), the gene encoding this receptor on chromosome 8 contains two exons and one intron enabling alternative splicing and formation of two different receptor isoforms with different pharmacologic properties.3Second, the β3-AR lacks phosphorylation sites for G protein–coupled receptor kinase and protein kinase A in the cytoplasmic C-terminus tail, and thus is resistant to catecholamine-induced desensitization.4Third, besides the strong lusitropic effects, the majority of studies suggest inhibition of cardiac contractility after β3-AR stimulation. Hence, in the presence of labetalol or prazosin plus nadolol, i.e. , α- plus β1/2-AR blockade, norepinephrine becomes cardiodepressive.5In cardiomyocytes (fig. 1), β3-ARs activate, through a pertussis toxin–sensitive Giprotein–coupled mechanism, endothelial nitric oxide synthase (eNOS or NOS3), located between sarcolemmal and T-tubular caveolae, and nNOS (or NOS1), located in the sarcoplasmic reticulum (or sarcolemma in the failing heart), and exert nitric oxide–mediated negative inotropic effects via the guanylyl cyclase–cyclic guanosine monophosphate pathway on L-type Ca2+channels and on myofilaments.5–8Nitric oxide further inhibits contractility by S-nitrosylation of key proteins of the respiratory chain,9energy metabolism,10contractile apparatus, and Ca2+handling, and it potentiates the inhibitory effect of the Gi protein on protein kinase A by activating phosphodiesterase II,11thereby reducing the second messenger cyclic adenosine monophosphate of the Gs-coupled β1/2-ARs. A last feature of the β3-AR is its low expression in healthy myocardium with a preference in left ventricular tissue, while its expression is reported to increase by two to three times in various pathologic conditions including sepsis,12diabetes,13and heart failure14and, as shown in the current study by Birenbaum et al. ,1during the aging process.In perioperative medicine, the sympathetic nervous system plays an important role in the pathogenesis of cardiovascular complications.15Therefore, gaining control over the adrenergic activity represents a core task in anesthetic practice.16,17On the other side, sustained activation of the sympathetic nervous system with enhanced β-AR signaling plays an important role in cardiovascular aging by promoting inflammation, oxidation and nitrosylation of key proteins, and cell death.18Consistent with the free radical theory of aging, previous studies showed increased formation of reactive oxygen and nitrogen species in aged myocardium, mainly generated by mitochondria and nitric oxide synthase (NOS) isoforms.19Nitric oxide is produced by nearly all cell types in the heart, and is synthesized from l-arginine by the catalytic reaction of the three different highly compartmentalized isoforms of nitric oxide synthase (neuronal or type 1 NOS [nNOS or NOS1], inducible or type 2 NOS [iNOS or NOS2], and endothelial or type 3 NOS [eNOS or NOS3]).20In the aged heart, iNOS and nNOS, mainly found in cardiomyocytes and autonomic nerves, are up-regulated, whereas eNOS, primarily expressed in endothelial cells (but also myocytes), is down-regulated.21,22In the adult heart, nitric oxide regulates cardiac biology by affecting energy metabolism, substrate utilization, apoptosis, hypertrophy, regeneration, and preconditioning.23However, its biologic effects are often “double-edged,” with a variety of opposing effects depending on the dose and site of action within the cell. Li et al. 24demonstrated the deleterious effects of nitric oxide derived from up-regulated iNOS in isolated perfused aged versus young rat hearts. These authors found increased nitric oxide and peroxynitrite formation deriving from up-regulated iNOS, which aggravated postischemic cardiac dysfunction and enlarged infarct size under β-AR stimulation with isoproterenol in aged versus young hearts. nNOS expression was also increased in aged hearts in that study, but its contribution to isoproterenol-induced postischemic damage was not investigated. Nonetheless, this study provides evidence that a phenotypic change of NOS isoforms in aged hearts may predispose to increased myocardial damage under sympathetic tone. As can be speculated from the results by Birenbaum et al. ,1the observed detrimental effect in the study of Li et al. 24may be well explained by upregulation of β3-ARs. Augmented cardiac nitric oxide formation by β3-AR signaling was also reported to be deleterious in sepsis, where the release of endogenous inflammatory mediators such as tumor necrosis factor α and interleukin 1β dramatically decrease the responsiveness of cardiomyocytes to catecholamines.12Interestingly, this refractoriness to catecholamines is absent in septic β3-AR knockout mice.12In contrast to the toxic effects of β3-AR signaling in certain conditions, in healthy adult hearts, β3-AR signaling is necessary to counteract the proarrhythmogenic, and otherwise unchained chronotropic, dromotropic, and inotropic effects of β1/2-ARs.8This phylogenetically highly conserved and protective negative feedback loop against catecholamine toxicity is important for a balanced and fine-tuned contractility.8Generally speaking, β3-AR signaling acts as a countervailing “brake” against adrenergic overstimulation comparable with an “endogenous”β blockade. This concept is further supported by the fact that β3-ARs maintain cardiac sympathovagal balance by reinforcing vagal tone. Beyond these benefits, but in contrast to pure β blockade, nitric oxide from β3-AR signaling further exerts coronary and peripheral vasodilatation, and may have “pleiotropic” effects on cardiac stem cell biology25and the prevention of arteriosclerosis.26Indeed, the “pharmacologic profile” of β3-AR signaling strongly reminds of the one observed with the novel third-generation β-blocker nebivolol, which promotes nitric oxide formation.27Research in the field of heart failure also supports the idea that β3-AR signaling is beneficial rather than detrimental. In the failing heart, the β3-AR response is preserved even under sustained activation of the adrenergic system and thus antagonizes catecholamine toxicity. However, this does not exclude that adverse effects do occur from β3-AR–mediated negative inotropy, particularly during the progression of heart failure. Interestingly, β3-AR knockout mice show increased SERCA2a expression and phospholamban phosphorylation resulting in enhanced SERCA2a activity.28Hence, one could speculate that β3-AR blockade could play a salutary role in the therapy of heart failure, at least at later stages of the disease. Together, the biologic consequences of enhanced β3-AR signaling range from “nitric oxide intoxication” on one side to protection comparable to some sort of “physiologic” or “endogenous”β-blockade on the other side. Although the study by Birenbaum et al. 1shows undesirable short-term effects of enhanced β3-AR signaling on inotropy in aged hearts, the biologic (long-term) consequences of this pathway remain elusive.A number of important questions need to be addressed in future studies before we can translate the findings of Birenbaum et al. to the clinical arena. First, based on genome-wide transcriptional profiling, the molecular mechanisms involved in reduced β-adrenergic responsiveness in the aged heart seem to be more complex and not just confined to a single signaling pathway. Accordingly, Dobson et al. 29reported up-regulation of 19 transcripts involved in age-related antiadrenergic activity, including adenosine A1, muscarinic M3, and nicotinic β3acetylcholine receptors, and many more. Second, female tissue was reported to express less β3-ARs,30and nitric oxide is differentially regulated in male and female hearts, as evidenced in nNOS knockout mice, where males develop more pronounced cardiac remodeling than females.31Therefore, sex-based differences may be of relevance in β3-AR and nitric oxide signaling, specifically in aged hearts. Third, although the rat and human β3-AR share 79% identity, there are pronounced heterogeneous pharmacologic profiles of β3-AR agonists/antagonists between different species. Therefore, caution must be applied in extrapolating data obtained from rat hearts to human myocardium. Finally, β3-ARs are also expressed in vessels. Namely, β3-ARs are expressed on the endothelium of coronary microarteries,32but their role in ischemia–reperfusion is unknown, and it is unclear, to date, whether vascular β3-ARs are similarly up-regulated during the aging process.Modulation of β3-AR signaling in the diseased heart in general and in the senescent heart in particular opens new therapeutic approaches. However, much research is required to fully understand the complexity of β-AR biology with its contrasting influences. New compounds with β3-AR agonistic and/or antagonistic properties could help to better modulate and control the adrenergic system in the perioperative period. For example, in coronary artery bypass graft surgery patients, there is β1/2-AR but not β3-AR dysfunction after cardiopulmonary bypass, and β3-AR stimulation could increase graft flow, decrease oxygen consumption, and thus protect the heart. However, these effects must be carefully balanced against the negative inotropy of β3-AR signaling. Interestingly, the single nucleotide polymorphism of the β3-AR at codon 64 from tryptophan to arginine was found to be associated with insulin resistance, diabetes, obesity, and hypertension.8Hence, patient studies investigating the impact of β-AR genomics on cardiac biology and clinical outcome might help to discern the therapeutic potential of β3-AR signaling in the context of other important adrenergic polymorphisms33in human heart disease. Clearly, the findings by Birenbaum et al. 1are important and will stimulate future research aiming at improving the cardiovascular management of elderly surgical at-risk patients. In this challenging endeavor, however, we need to expand our understanding of complex β-AR signaling beyond the platitude that “it is not by the gray of the hair that one knows the age of the heart” (Robert Bulwer-Lytton).*Department of Anesthesiology and Pain Medicine, University of Alberta, and Perioperative Translational Medicine, Mazankowski Alberta Heart Institute, Edmonton, Canada. michael.zaugg@ualberta.ca. †Institute of Pharmacology, University of Zurich, Switzerland." @default.
• W1972506323 created "2016-06-24" @default.
• W1972506323 creator A5020380292 @default.
• W1972506323 creator A5089467033 @default.
• W1972506323 date "2008-12-01" @default.
• W1972506323 modified "2023-09-23" @default.
• W1972506323 title "β3-Adrenergic Receptor Subtype Signaling In Senescent Heart" @default.
• W1972506323 cites W189136505 @default.
• W1972506323 cites W1891677971 @default.
• W1972506323 cites W1967095406 @default.
• W1972506323 cites W1967951942 @default.
• W1972506323 cites W1979026148 @default.
• W1972506323 cites W1980336437 @default.
• W1972506323 cites W1980773099 @default.
• W1972506323 cites W1990215202 @default.
• W1972506323 cites W1991074341 @default.
• W1972506323 cites W2008272689 @default.
• W1972506323 cites W2009408345 @default.
• W1972506323 cites W2012863869 @default.
• W1972506323 cites W2013287363 @default.
• W1972506323 cites W2019402170 @default.
• W1972506323 cites W2021379446 @default.
• W1972506323 cites W2032742408 @default.
• W1972506323 cites W2046610430 @default.
• W1972506323 cites W2065117159 @default.
• W1972506323 cites W2067979102 @default.
• W1972506323 cites W2074697641 @default.
• W1972506323 cites W2087047630 @default.
• W1972506323 cites W2088811866 @default.
• W1972506323 cites W2090041904 @default.
• W1972506323 cites W2097149135 @default.
• W1972506323 cites W2097750015 @default.
• W1972506323 cites W2105928696 @default.
• W1972506323 cites W2112033406 @default.
• W1972506323 cites W2117031715 @default.
• W1972506323 cites W2120062223 @default.
• W1972506323 cites W2131399515 @default.
• W1972506323 cites W2133556432 @default.
• W1972506323 cites W2136940916 @default.
• W1972506323 cites W2157800645 @default.
• W1972506323 cites W2168627568 @default.
• W1972506323 doi "https://doi.org/10.1097/aln.0b013e31818d4942" @default.
• W1972506323 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19034090" @default.
• W1972506323 hasPublicationYear "2008" @default.
• W1972506323 type Work @default.
• W1972506323 sameAs 1972506323 @default.
• W1972506323 citedByCount "4" @default.
• W1972506323 countsByYear W19725063232017 @default.
• W1972506323 countsByYear W19725063232019 @default.
• W1972506323 crossrefType "journal-article" @default.
• W1972506323 hasAuthorship W1972506323A5020380292 @default.
• W1972506323 hasAuthorship W1972506323A5089467033 @default.
• W1972506323 hasBestOaLocation W19725063231 @default.
• W1972506323 hasConcept C121528942 @default.
• W1972506323 hasConcept C126322002 @default.
• W1972506323 hasConcept C134018914 @default.
• W1972506323 hasConcept C158453852 @default.
• W1972506323 hasConcept C169331234 @default.
• W1972506323 hasConcept C170493617 @default.
• W1972506323 hasConcept C178059049 @default.
• W1972506323 hasConcept C40465926 @default.
• W1972506323 hasConcept C46688247 @default.
• W1972506323 hasConcept C62478195 @default.
• W1972506323 hasConcept C71924100 @default.
• W1972506323 hasConcept C86803240 @default.
• W1972506323 hasConcept C95444343 @default.
• W1972506323 hasConceptScore W1972506323C121528942 @default.
• W1972506323 hasConceptScore W1972506323C126322002 @default.
• W1972506323 hasConceptScore W1972506323C134018914 @default.
• W1972506323 hasConceptScore W1972506323C158453852 @default.
• W1972506323 hasConceptScore W1972506323C169331234 @default.
• W1972506323 hasConceptScore W1972506323C170493617 @default.
• W1972506323 hasConceptScore W1972506323C178059049 @default.
• W1972506323 hasConceptScore W1972506323C40465926 @default.
• W1972506323 hasConceptScore W1972506323C46688247 @default.
• W1972506323 hasConceptScore W1972506323C62478195 @default.
• W1972506323 hasConceptScore W1972506323C71924100 @default.
• W1972506323 hasConceptScore W1972506323C86803240 @default.
• W1972506323 hasConceptScore W1972506323C95444343 @default.
• W1972506323 hasIssue "6" @default.
• W1972506323 hasLocation W19725063231 @default.
• W1972506323 hasLocation W19725063232 @default.
• W1972506323 hasLocation W19725063233 @default.
• W1972506323 hasOpenAccess W1972506323 @default.
• W1972506323 hasPrimaryLocation W19725063231 @default.
• W1972506323 hasRelatedWork W1977589856 @default.
• W1972506323 hasRelatedWork W2025094058 @default.
• W1972506323 hasRelatedWork W2027321041 @default.
• W1972506323 hasRelatedWork W2169164259 @default.
• W1972506323 hasRelatedWork W2217999767 @default.
• W1972506323 hasRelatedWork W2382428708 @default.
• W1972506323 hasRelatedWork W3174686875 @default.
• W1972506323 hasRelatedWork W3203317871 @default.
• W1972506323 hasRelatedWork W4245315843 @default.
• W1972506323 hasRelatedWork W926668978 @default.
• W1972506323 hasVolume "109" @default.
• W1972506323 isParatext "false" @default.
• W1972506323 isRetracted "false" @default.

• next