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Dual-omics reveals the different roles of α1 and β-adrenergic receptors in acute sympathetic stress-induced cardiac inflammation

ABSTRACT: Sympathetic overactivation under strong acute stresses triggers acute cardiovascular events including myocardial infarction (MI), sudden cardiac death, and stress cardiomyopathy. α1-ARs and β-ARs, two dominant subtypes of adrenergic receptors in the heart, play a significant role in the physiological and pathologic regulation of these processes. However, little is known about the functional similarities and differences between α1- and β-ARs activated temporal responses in stress-induced cardiac pathology. In this work, we systematically compared the cardiac temporal genome-wide profiles of acute α1-AR and β-AR activation in the mice model by integrating transcriptome and proteome. We found that α1- and β-AR activations induced sustained and transient inflammatory gene expression, respectively. Particularly, the overactivation of α1-AR but not β-AR led to neutrophil infiltration at 1 day, which was closely associated with the up-regulation of chemokines, activation of NF-κB pathway, and sustained inflammatory response. Furthermore, there are more metabolic disorders under α1-AR overactivation compared with β-AR overactivation. These findings provide a new therapeutic strategy that besides using β-blocker as soon as possible, blocking α1-AR within one day should also be considered in the treatment of acute stress associated cardiovascular diseases.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Di Zhang

LAB HEAD: Han Xiao

PROVIDER: PXD036011 | Pride | 2023-01-19

REPOSITORIES: Pride

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Project description:Aims: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Chronic β-AR activation causes maladaptive alterations in cardiomyocyte metabolism that contribute to the pathobiology of heart failure. In contrast, mounting evidence suggests that a1-ARs, particularly the a1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared endogenous catecholamine ligands. The mechanisms through which a1A-ARs exert their cardioprotective effects remain unclear. Here we tested the hypothesis that a1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and failing heart. Methods: We characterized the effects of global α1A-AR genetic deletion on mitochondrial function and metabolism in the uninjured mouse heart using high resolution respirometry, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM), proteomics, and lipidomics. We then compared the effects of α1A- and β-AR agonist treatment on ETC enzyme activity and oxidative stress in vivo and in vitro. We subjected wild type and cardiomyocyte-specific α1A-KO mice to permanent left coronary artery (LCA) ligation and used RNAseq to compare the transcriptomic response. Results: We found that isolated cardiac mitochondria from mice with global α1A-AR genetic deletion (α1A-KO) had deficits in fatty acid-dependent respiration and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 (100 ng/kg/d, 3d) enhanced fatty acid oxidation (FAO) in isolated cardiac mitochondria while increasing expression and activity of the mitochondrial trifunctional protein, a critical FAO mediator. The β-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. RNAseq revealed broad basal deficits in pathways related to mitochondria and OXPHOS in cardiomyocyte-specific α1A-KO mice; these differences were exaggerated by LCA ligation. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. Conclusions: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Project description:This a model from the article: Compartmentation of cAMP signaling in cardiac myocytes: a computational study. Iancu RV, Jones SW, Harvey RD. Biophys J 2007 May 1;92(9):3317-31 17293406 , Abstract: Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In this study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of beta(1)-adrenergic receptor (beta(1)AR) and M(2) muscarinic receptor (M(2)R) activation involve compartmentation of cAMP. A model consisting of two submembrane (caveolar and extracaveolar) microdomains and one bulk cytosolic domain was created using published information on the location of beta(1)ARs and M(2)Rs, as well as the location of stimulatory (G(s)) and inhibitory (G(i)) G-proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by G(i), and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high ( approximately 1 microM) and only modestly stimulated by beta(1)AR activation ( approximately 2 microM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A ( approximately 100 nM to approximately 2 microM); 2), M(2)R activation strongly reduces the beta(1)AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak beta(1)AR stimulation, M(2)R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M(2)R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Iancu RV, Jones SW, Harvey RD. (2007) - version=1.0 The original CellML model was created by: Geoffrey Nunns gnunns1@jhu.edu The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Dual-omics reveals the different roles of α1 and β-adrenergic receptors in acute sympathetic stress-induced cardiac inflammation

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