An Analysis of the Myocardial Transcriptome in a Mouse Model of Cardiac Dysfunction with Decreased Cholinergic Neurotransmission

Roy, Amrita; Lara, Aline; Guimarães, Diogo; Pires, Rita Gomes Wanderley; Gomes, Enéas Ricardo de Morais; Carter, David E.; Gomez, Marcus V.; Guatimosim, Sílvia; Prado, Vânia F.; Prado, Marco A. M.; Gros, Robert

doi:10.1371/journal.pone.0039997

Cited by 9 publications

(15 citation statements)

References 36 publications

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“…ROS levels were measured using the MitoSOX Red superoxide indicator (Invitrogen, Carlsbad, CA, USA), as described previously (17).…”

Section: Methodsmentioning

confidence: 99%

“…Adult cardiomyocytes were isolated and calcium transients were recorded as described previously (3, 17) using line‐scan imaging on a Zeiss LSM 510 Meta confocal microscope. Images were processed and Ca 2+ recordings were analyzed using ImageJ software.…”

Section: Methodsmentioning

confidence: 99%

“…RNA was extracted from isolated cardiomyocytes, and cDNA was synthesized as described previously (17). A brain sample was used as a positive control for VAChT, and a nontemplate reaction was used as a negative control.…”

Section: Qpcr/rt-pcrmentioning

confidence: 99%

“…A brain sample was used as a positive control for VAChT, and a nontemplate reaction was used as a negative control. qPCR for atrial natriuretic peptide (ANP) and G-protein-coupled receptor kinases 2 and 5 (GRK2 and GRK5) was performed as described previously (17). For primer sequences, see Supplemental Table S1.…”

Section: Qpcr/rt-pcrmentioning

confidence: 99%

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Cardiomyocyte‐secreted acetylcholine is required for maintenance of homeostasis in the heart

et al. 2013

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Heart activity and long-term function are regulated by the sympathetic and parasympathetic branches of the nervous system. Parasympathetic neurons have received increased attention recently because acetylcholine (ACh) has been shown to play protective roles in heart disease. However, parasympathetic innervation is sparse in the heart, raising the question of how cholinergic signaling regulates cardiomyocytes. We hypothesized that non-neuronal secretion of ACh from cardiomyocytes plays a role in cholinergic regulation of cardiac activity. To test this possibility, we eliminated secretion of ACh exclusively from cardiomyocytes by targeting the vesicular acetylcholine transporter (VAChT). We find that lack of cardiomyocyte-secreted ACh disturbs the regulation of cardiac activity and causes cardiomyocyte remodeling. Mutant mice present normal hemodynamic parameters under nonstressful conditions; however, following exercise, their heart rate response is increased. Moreover, hearts from mutant mice present increased oxidative stress, altered calcium signaling, remodeling, and hypertrophy. Hence, without cardiomyocyte-derived ACh secretion, hearts from mutant mice show signs of imbalanced autonomic activity consistent with decreased cholinergic drive. These unexpected results suggest that cardiomyocyte-derived ACh is required for maintenance of cardiac homeostasis and regulates critical signaling pathways necessary to maintain normal heart activity. We propose that this non-neuronal source of ACh boosts parasympathetic cholinergic signaling to counterbalance sympathetic activity regulating multiple aspects of heart physiology.

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“…ROS levels were measured using the MitoSOX Red superoxide indicator (Invitrogen, Carlsbad, CA, USA), as described previously (17).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Qpcr/rt-pcrmentioning

confidence: 99%

Section: Qpcr/rt-pcrmentioning

confidence: 99%

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Cardiomyocyte‐secreted acetylcholine is required for maintenance of homeostasis in the heart

et al. 2013

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“…This glycoprotein is overexpressed in DHF and significantly increased in treated heart. The ribonuclease family was significantly decreased in the ventricles obtained from the vesicular acetylcholine transporter in genetically modified homozygous mice, which led to symptoms resembling cardiac dysfunction . In summary, these circulating glycoproteins play a variety of roles in the metabolic pathways, thus they could be candidates for HF due to left ventricular dyssynchrony.…”

Section: Discussionmentioning

confidence: 99%

Glycoproteins identified from heart failure and treatment models

et al. 2014

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Conduction abnormalities can lead to dyssynchronous contraction, which significantly worsens morbidity and mortality of heart failure. Cardiac resynchronization therapy (CRT) can reverse ventricular remodeling and improve cardiac function. Although the underlying molecular changes are unknown, the use of a canine model of dyssynchrony heart failure (DHF) and CRT has shown that there are global changes across the cardiac proteome. This study determines changes in serum glycoprotein concentration from DHF and CRT compared to normal. We hypothesize that CRT invokes protective or advantageous pathways that can be reflected in the circulating proteome. A two prong discovery approaches were carried out on pooled normal, DHF and CRT samples composed of individual canine serum to determine the overall protein concentration and the N-linked glycosites of circulating glycoproteins. The level of the glycoproteins was altered in DHF and CRT compared to control sera, with 63 glycopeptides substantially increased in DHF and/or CRT. Among the 32 elevated glycosite-containing peptides in DHF, 13 glycopeptides were reverted to normal level after CRT therapy. We further verify the changes of glycopeptides using label-free LC-MS from individual canine serum. Circulating glycoproteins such as alpha-fetoprotein, alpha-2-macroglobulin, galectin-3-binding protein, collectin-10 show association to failing heart and CRT treatment model.

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Regulation of cholinergic activity by the vesicular acetylcholine transporter

Prado

Roy

Kolisnyk

et al. 2013

Biochemical Journal

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113

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Acetylcholine, the first chemical to be identified as a neurotransmitter, is packed in synaptic vesicles by the activity of VAChT (vesicular acetylcholine transporter). A decrease in VAChT expression has been reported in a number of diseases, and this has consequences for the amount of acetylcholine loaded in synaptic vesicles as well as for neurotransmitter release. Several genetically modified mice targeting the VAChT gene have been generated, providing novel models to understand how changes in VAChT affect transmitter release. A surprising finding is that most cholinergic neurons in the brain also can express a second type of vesicular neurotransmitter transporter that allows these neurons to secrete two distinct neurotransmitters. Thus a given neuron can use two neurotransmitters to regulate different physiological functions. In addition, recent data indicate that non-neuronal cells can also express the machinery used to synthesize and release acetylcholine. Some of these cells rely on VAChT to secrete acetylcholine with potential physiological consequences in the periphery. Hence novel functions for the oldest neurotransmitter known are emerging with the potential to provide new targets for the treatment of several pathological conditions.

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An Analysis of the Myocardial Transcriptome in a Mouse Model of Cardiac Dysfunction with Decreased Cholinergic Neurotransmission

Cited by 9 publications

References 36 publications

Cardiomyocyte‐secreted acetylcholine is required for maintenance of homeostasis in the heart

Cardiomyocyte‐secreted acetylcholine is required for maintenance of homeostasis in the heart

Glycoproteins identified from heart failure and treatment models

Regulation of cholinergic activity by the vesicular acetylcholine transporter

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