Stimulation of P2Y11 receptor modulates cardiac fibroblasts secretome toward immunomodulatory and protective roles after Hypoxia/Reoxygenation injury

Lefort, Corinne; Benoist, Lauriane; Chadet, Stéphanie; Piollet, Marie; Héraud, Audrey; Babuty, Dominique; Baron, Christophe; Ivanès, Fabrice; Angoulvant, Denis

doi:10.1016/j.yjmcc.2018.07.245

Cited by 15 publications

(17 citation statements)

References 33 publications

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“…Although previous studies have evaluated the effect of simulated I/R (sI/R) on CF death [12][13][14][15], the impact of oxidative stress triggered by reperfusion injury on the functional capacity associated with fibroblast-mediated tissue repair, remains to be fully elucidated. In this context, the use of antioxidants to confer cardioprotection in patients with MI subjected to percutaneous coronary angioplasty has been previously reviewed [6,8,16].…”

Section: Introductionmentioning

confidence: 99%

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

Parra-Flores

Riquelme

Valenzuela-Bustamante

et al. 2019

Antioxidants

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Acute myocardial infarction is one of the leading causes of death worldwide and thus, an extensively studied disease. Nonetheless, the effects of ischemia/reperfusion injury elicited by oxidative stress on cardiac fibroblast function associated with tissue repair are not completely understood. Ascorbic acid, deferoxamine, and N-acetylcysteine (A/D/N) are antioxidants with known cardioprotective effects, but the potential beneficial effects of combining these antioxidants in the tissue repair properties of cardiac fibroblasts remain unknown. Thus, the aim of this study was to evaluate whether the pharmacological association of these antioxidants, at low concentrations, could confer protection to cardiac fibroblasts against simulated ischemia/reperfusion injury. To test this, neonatal rat cardiac fibroblasts were subjected to simulated ischemia/reperfusion in the presence or absence of A/D/N treatment added at the beginning of simulated reperfusion. Cell viability was assessed using trypan blue staining, and intracellular reactive oxygen species (ROS) production was assessed using a 2′,7′-dichlorofluorescin diacetate probe. Cell death was measured by flow cytometry using propidium iodide. Cell signaling mechanisms, differentiation into myofibroblasts and pro-collagen I production were determined by Western blot, whereas migration was evaluated using the wound healing assay. Our results show that A/D/N association using a low concentration of each antioxidant increased cardiac fibroblast viability, but that their separate administration did not provide protection. In addition, A/D/N association attenuated oxidative stress triggered by simulated ischemia/reperfusion, induced phosphorylation of pro-survival extracellular-signal-regulated kinases 1/2 (ERK1/2) and PKB (protein kinase B)/Akt, and decreased phosphorylation of the pro-apoptotic proteins p38- mitogen-activated protein kinase (p38-MAPK) and c-Jun-N-terminal kinase (JNK). Moreover, treatment with A/D/N also reduced reperfusion-induced apoptosis, evidenced by a decrease in the sub-G1 population, lower fragmentation of pro-caspases 9 and 3, as well as increased B-cell lymphoma-extra large protein (Bcl-xL)/Bcl-2-associated X protein (Bax) ratio. Furthermore, simulated ischemia/reperfusion abolished serum-induced migration, TGF-β1 (transforming growth factor beta 1)-mediated cardiac fibroblast-to-cardiac myofibroblast differentiation, and angiotensin II-induced pro-collagen I synthesis, but these effects were prevented by treatment with A/D/N. In conclusion, this is the first study where a pharmacological combination of A/D/N, at low concentrations, protected cardiac fibroblast viability and function after simulated ischemia/reperfusion, and thereby represents a novel therapeutic approach for cardioprotection.

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Section: Introductionmentioning

confidence: 99%

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

Parra-Flores

Riquelme

Valenzuela-Bustamante

et al. 2019

Antioxidants

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“…They also found that conditioned media from cultured cardiac fibroblasts subjected to hypoxia and reoxygenation did not protect cardiac myocytes from IR damage, while factors from other non-myocytes of mesenchymal origin did [40]; however, these authors did not consider IR injury beyond changes associated with fibroblast death, or IPC, in their model. Lefort et al [41] reported that cultured human ventricular fibroblasts produced secretomes in response to 5 h of hypoxia and 24 h reoxygenation, which reduced cardiac myocyte death during the hypoxia/ reoxygenation challenge. These authors also reported that stimulation of the metabotropic purine P2Y11 receptor in cultured human ventricular fibroblasts at the onset of reoxygenation reduced fibroblast to myofibroblast differentiation [41], suggesting that Gq and Gs protein-coupled pathways modulate fibroblast differentiation in response to hypoxia and reoxygenation.…”

Section: Discussionmentioning

confidence: 99%

“…Lefort et al [41] reported that cultured human ventricular fibroblasts produced secretomes in response to 5 h of hypoxia and 24 h reoxygenation, which reduced cardiac myocyte death during the hypoxia/ reoxygenation challenge. These authors also reported that stimulation of the metabotropic purine P2Y11 receptor in cultured human ventricular fibroblasts at the onset of reoxygenation reduced fibroblast to myofibroblast differentiation [41], suggesting that Gq and Gs protein-coupled pathways modulate fibroblast differentiation in response to hypoxia and reoxygenation.…”

Section: Discussionmentioning

confidence: 99%

Ischemia Reperfusion Injury Produces, and Ischemic Preconditioning Prevents, Rat Cardiac Fibroblast Differentiation: Role of KATP Channels

Pertiwi

Hillman

Scott

et al. 2019

JCDD

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Ischemic preconditioning (IPC) and activation of ATP-sensitive potassium channels (KATP) protect cardiac myocytes from ischemia reperfusion (IR) injury. We investigated the influence of IR injury, IPC and KATP in isolated rat cardiac fibroblasts. Hearts were removed under isoflurane anesthesia. IR was simulated in vitro by application and removal of paraffin oil over pelleted cells. Ischemia (30, 60 and 120 min) followed by 60 min reperfusion resulted in significant differentiation of fibroblasts into myofibroblasts in culture (mean % fibroblasts ± SEM in IR vs. time control: 12 ± 1% vs. 63 ± 2%, 30 min ischemia; 15 ± 3% vs. 71 ± 4%, 60 min ischemia; 8 ± 1% vs. 55 ± 2%, 120 min ischemia). IPC (15 min ischemia, 30 min reperfusion) significantly attenuated IR-induced fibroblast differentiation (52 ± 3%) compared to 60 min IR. IPC was mimicked by opening KATP with pinacidil (50 μM; 43 ± 6%) and by selectively opening mitochondrial KATP (mKATP) with diazoxide (100 μM; 53 ± 3%). Furthermore, IPC was attenuated by inhibiting KATP with glibenclamide (10 μM; 23 ± 5%) and by selectively blocking mKATP with 5-hydroxydecanoate (100 μM; 22 ± 9%). These results suggest that (a) IR injury evoked cardiac fibroblast to myofibroblast differentiation, (b) IPC attenuated IR-induced fibroblast differentiation, (c) KATP were involved in IPC and (d) this protection involved selective activation of mKATP.

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“…Although prolonged neutrophil recruitment is detrimental, neutrophils are required to initiate the reparative process that occurs 4-14 days post MI [184,205]. Of note, P2Y11R stimulation in CFs may be beneficial; conditioned medium from human CFs treated with the P2Y11R agonist NF546 promotes pro-survival signaling in CMs subjected to hypoxia/ reoxygenation (H/R) injury by activating the RISK pathway [224]. Furthermore, the secretome of P2Y11R stimulated CFs suppresses dendritic cell activation by LPS [224].…”

Section: Intercellular Communicationmentioning

confidence: 99%

“…Of note, P2Y11R stimulation in CFs may be beneficial; conditioned medium from human CFs treated with the P2Y11R agonist NF546 promotes pro-survival signaling in CMs subjected to hypoxia/ reoxygenation (H/R) injury by activating the RISK pathway [224]. Furthermore, the secretome of P2Y11R stimulated CFs suppresses dendritic cell activation by LPS [224]. H/R injury likely promotes CF-mediated protection of CMs through multiple factors.…”

Section: Intercellular Communicationmentioning

confidence: 99%

Protective transcriptional mechanisms in cardiomyocytes and cardiac fibroblasts

Brand

Lighthouse

Trembley

2019

Journal of Molecular and Cellular Cardiology

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Heart failure is the leading cause of morbidity and mortality worldwide. Several lines of evidence suggest that physical activity and exercise can precondition the heart to improve the response to acute cardiac injury such as myocardial infarction or ischemia/reperfusion injury, preventing the progression to heart failure. It is becoming more apparent that cardioprotection is a concerted effort between multiple cell types and converging signaling pathways. However, the molecular mechanisms of cardioprotection are not completely understood. What is clear is that the mechanisms underlying this protection involve acute activation of transcriptional activators and their corresponding gene expression programs. Here, we review the known stress-dependent transcriptional programs that are activated in cardiomyocytes and cardiac fibroblasts to preserve function in the adult heart after injury. Focus is given to prominent transcriptional pathways such as mechanical stress or reactive oxygen species (ROS)-dependent activation of myocardin-related transcription factors (MRTFs) and transforming growth factor beta (TGFβ), and gene expression that positively regulates protective PI3K/Akt signaling. Together, these pathways modulate both beneficial and pathological responses to cardiac injury in a cell-specific manner.

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Stimulation of P2Y11 receptor modulates cardiac fibroblasts secretome toward immunomodulatory and protective roles after Hypoxia/Reoxygenation injury

Cited by 15 publications

References 33 publications

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

Ischemia Reperfusion Injury Produces, and Ischemic Preconditioning Prevents, Rat Cardiac Fibroblast Differentiation: Role of KATP Channels

Protective transcriptional mechanisms in cardiomyocytes and cardiac fibroblasts

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