Sympathetic Nervous System Signaling in Heart Failure and Cardiac Aging

Santulli, Gaetano

doi:10.1007/978-3-319-15961-4_5

Cited by 9 publications

(9 citation statements)

References 135 publications

(74 reference statements)

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“…Hyperactivation of sympathetic nervous system in HF is initially compensatory, but eventually accelerates the progression of the disease, posing severe toxicity on the chronically failing heart [107,108,111]. In this sense, the beneficial effects of AR blockers and other therapeutic approaches that mitigate or protect the heart against this sympathetic overdrive are well documented [108,112,113].…”

Section: Ryr2 and Heart Failurementioning

confidence: 99%

Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Santulli

Marks

2015

CMP

Self Cite

177

165

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Calcium (Ca(2+)) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca(2+) release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca(2+) release. Here we focus on the roles of CRCs in heart, skeletal muscle, brain, metabolism, and aging.

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Section: Ryr2 and Heart Failurementioning

confidence: 99%

Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Santulli

Marks

2015

CMP

Self Cite

177

165

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“…Our present findings add a novel mechanism for OPN’s pro-fibrotic effects, at least in the heart— interference with the anti-fibrotic actions of the catecholamines through the β 2 AR. In contrast to the β 1 AR, the β 2 AR is considered cardio-protective in the post-MI failing heart, since it can facilitate infarct (wound) healing; promote cardiomyocyte survival; and limit inflammation, apoptosis, and other adverse remodeling processes that ensue immediately after an MI [4,39,40]. Indeed, cAMP and its effector Epac1—which are induced by the activated β 2 AR in the heart—are known to exert anti-fibrotic effects in several cell types and tissues, including in the heart [16].…”

Section: Discussionmentioning

confidence: 99%

Deletion of Osteopontin Enhances β2-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes

Pollard

Desimine

Wertz

et al. 2019

IJMS

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Cardiac β2-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β2AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates the generation of cyclic 3′,5′-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inflammatory cytokine, which also mediates fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts—an effect prevented by endogenous β2AR activation. Additionally, CRISPR-mediated OPN deletion enhanced cAMP generation in response to both β1AR and β2AR activation in H9c2 cardiomyocytes, leading to the upregulation of Epac1 protein levels. These effects rendered β2AR stimulation capable of completely abrogating transforming growth factor (TGF)-β-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacted constitutively with Gαs subunits in H9c2 cardiac cells. Thus, we uncovered a direct inhibitory role of OPN in cardiac β2AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.

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“…Adrenergic receptors (ARs) belong to the family of G protein-coupled receptors (GPCRs). Reportedly, ARs are involved in aging and cardiovascular physiopathology (15). In response to stimulation of the sympathetic nervous system, α 1 ARs (α 1A , α 1B and α 1D ) are able to activate Gα q , which contributes to cardiac remodeling (16).…”

Section: Discussionmentioning

confidence: 99%

An RNA‑sequencing study identifies candidate genes for angiotensin II‑induced cardiac remodeling

Jin

Liu

et al. 2017

Mol Med Report

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The present study aimed to reveal the underlying mechanism of angiotensin II (AngII)‑induced cardiac remodeling and to identify potential therapeutic targets for prevention. Rat cardiac fibroblasts (CFs) were cultured with 10 nM AngII for 12 h, and CFs without AngII were used as the control. Following RNA isolation from AngII treated and control CFs, RNA‑sequencing was performed to detect gene expression levels. Differentially‑expressed genes (DEGs) were identified using the linear models for microarray analysis package in R software, and their functions and pathways were examined via enrichment analysis. In addition, potential associations at the protein level were revealed via the construction of a protein‑protein interaction (PPI) network. The expression levels of genes of interest were validated via reverse transcription‑quantitative polymerase chain reaction analysis. In total, 126 upregulated and 140 downregulated DEGs were identified. According to the enrichment analysis, acetyl coA carboxylase β (ACACB), interleukin 1β (IL1B), interleukin 1α (IL1A), nitric oxide synthase 2 (NOS2) and matrix metallopeptidase 3 (MMP3) were associated with the immune response, regulation of angiogenesis, superoxide metabolic process and carboxylic acid binding biological processes. Among them, ACACB and MPP3 were two predominant nodes in the PPI network. In addition, IL1B and MMP3 were demonstrated to be upregulated. These five genes, particularly IL1B and MMP3, may be used as candidate markers for the prevention of AngII‑induced cardiac remodeling.

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Sympathetic Nervous System Signaling in Heart Failure and Cardiac Aging

Cited by 9 publications

References 135 publications

Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Deletion of Osteopontin Enhances β2-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes

An RNA‑sequencing study identifies candidate genes for angiotensin II‑induced cardiac remodeling

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