Reduced expression of let‐7f activates <scp>TGF</scp>‐β/<scp>ALK</scp>5 pathway and leads to impaired ischaemia‐induced neovascularization after cigarette smoke exposure

Dhahri, Wahiba; Dussault, Sylvie; Haddad, Peter; Turgeon, Julie; Tremblay, Sophie; Rolland, Kevin; Desjarlais, Michel; Cáceres-Gorriti, Katia Y; Mathieu, Raphaël; Rivard, Alain

doi:10.1111/jcmm.13144

Cited by 26 publications

(28 citation statements)

References 46 publications

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“…A recent study from Dhahri et al . observed the reduced expression of let-7f in HUVECs treated with cigarette smoke extracts (CSE) and in the ischemic muscles of mice exposing to cigarette smoke, and they found that forced expression of let-7f promoted angiogenesis in HUVECs exposed to CSE by targeting TGF-βRI 31 . In this study, we also found the down-regulation of let-7f in the MI mice, which contains two potential binding sites for PFL.…”

Section: Discussionmentioning

confidence: 99%

LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d

Liang¹,

Pan²,

Zhao

et al. 2018

Theranostics

129

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Rationale: Cardiac fibrosis is associated with various cardiovascular diseases and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac diseases. However, the potential roles and underlying mechanisms of lncRNAs in cardiac fibrosis have not been explicitly delineated.Methods and Results: Using a combination of in vitro and in vivo studies, we identified a lncRNA NONMMUT022555, which is designated as a pro-fibrotic lncRNA (PFL), and revealed that PFL is up-regulated in the hearts of mice in response to myocardial infarction (MI) as well as in the fibrotic cardiac fibroblasts (CFs). We found that knockdown of PFL by adenoviruses carrying shRNA attenuated cardiac interstitial fibrosis and improved ejection fraction (EF) and fractional shortening (FS) in MI mice. Further study showed that forced expression of PFL promoted proliferation, fibroblast-myofibroblast transition and fibrogenesis in mice CFs by regulating let-7d, whereas silencing PFL mitigated TGF-β1-induced myofibroblast generation and fibrogenesis. More importantly, PFL acted as a competitive endogenous RNA (ceRNA) of let-7d, as forced expression of PFL reduced the expression and activity of let-7d. Moreover, let-7d levels were decreased in the MI mice and in fibrotic CFs. Inhibition of let-7d resulted in fibrogenesis in CFs, whereas forced expression of let-7d abated fibrogenesis through targeting platelet-activating factor receptor (Ptafr). Furthermore, overexpression of let-7d by adenoviruses carrying let-7d precursor impeded cardiac fibrosis and improved cardiac function in MI mice.Conclusion: Taken together, our study elucidated the role and mechanism of PFL in cardiac fibrosis, indicating the potential role of PFL inhibition as a novel therapy for cardiac fibrosis.

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Section: Discussionmentioning

confidence: 99%

LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d

Liang¹,

Pan²,

Zhao

et al. 2018

Theranostics

129

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“…12 months after anti-diabetic therapy, let-7f was normalized 48 . Not only high plasma glucose levels, but also immune activation by LPS or cigarette smoke provokes let-7f decreases 49 , 50 . The decrease in let-7f levels under cigarette smoke provoked anti-angiogenic effects via modulation TGFbeta-pathway in endothelial cells 50 .…”

Section: Discussionmentioning

confidence: 99%

“…Not only high plasma glucose levels, but also immune activation by LPS or cigarette smoke provokes let-7f decreases 49 , 50 . The decrease in let-7f levels under cigarette smoke provoked anti-angiogenic effects via modulation TGFbeta-pathway in endothelial cells 50 . Thus, the cellular source of the identified reductions in miRNA levels in atherosclerotic plaques may, primarily, come from ECs and VSMCs, and contribute to atherosclerosis progression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA expression profile of human advanced coronary atherosclerotic plaques

Parahuleva

Lipps

Parviz

et al. 2018

Sci Rep

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MicroRNA (miR) is reported to be involved in vascular inflammation and may represent a novel class of diagnostic biomarkers in cardiovascular disease. We aimed to identify the miR expression profile in human advanced coronary atherosclerotic plaques (CAP) and to connect this expression to the processes in atherosclerosis. Microarray techniques and TaqMan polymerase chain reaction were used to analyse the global expression of 352 miRs in CAP obtained during ACS MULTI-LINK study. 11 miRs were selected on the basis of their implication in atherosclerosis, endothelial activation, and inflammation. 6 miRs were found to be differently expressed in CAP when compared to non-atherosclerotic internal mammary arteries (IMA, p < 0.05). The expression of miR-21, -92a, and -99a was verified and found to be significantly up-regulated in CAP versus IMA (p < 0.001). We also performed bioinformatic analysis and found several potential target genes of miR-92a and -99a as well as several pathways with impact on atherosclerosis which could be differently expressed due to this miRNA profile. The most up-regulated miRs are involved in processes known to be connected to atherosclerosis. Interfering with the miR expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development.

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“…In our study two let‐7f miRNAs were regulated contrary after preconditioning with isoflurane, let‐7f‐2 was up‐regulated whereas let‐7f‐1‐3p was down‐regulated. Let‐7f is generally associated with myocardial infarction and angiogenesis [68,69]. The precise mechanisms and targets of our let‐7f miRNAs and their potential cardioprotective effects need to be unravelled in future studies [70–72].…”

Section: Discussionmentioning

confidence: 99%

Characterization of extracellular vesicles derived from cardiac cells in an in vitro model of preconditioning

Borosch

Dahmen

Beckers

et al. 2017

J of Extracellular Vesicle

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Preconditioning is a promising technique to protect the heart from ischaemia-reperfusion injury. In this context, the crosstalk between different cardiac cell types and especially the exchange of cardioprotective mediators has come into the focus of current research. Recently, extracellular vesicles (EVs), nano-sized structures, emerged as possible communication mediators. They are taken up by recipient cells and can alter gene expression or activate intracellular signal cascades. It has been shown that all cardiac cell types are able to secrete EVs, but so far the influence of an in vitro preconditioning stimulus on EV concentration and composition has not been investigated. Therefore, we stimulated primary cardiac myocytes and fibroblasts from neonatal rats, as well as H9c2 cells, with two known in vitro preconditioning stimuli: hypoxia or isoflurane. EVs were isolated from cell culture supernatants 48 h after stimulation by differential centrifugation and size exclusion chromatography. They were characterized by transmission electron microscopy, tunable resistive pulse sensing, miRNA array and Western blot analysis. The detected EVs had the typical cup-shaped morphology and a size of about 150 nm. No significant differences in EV concentration were observed between the different groups. The protein and miRNA load was affected by in vitro preconditioning with isoflurane or hypoxia. EV markers like Alix, CD63, flotillin-1 and especially heat shock protein 70 were significantly up-regulated by the treatments. Several miRNAs like miR-92b-3p, miR-761 and miR-101a-5p were also significantly affected. A migration assay confirmed the physiological benefit of these EVs. Taken together, our findings show that a model of in vitro preconditioning of cardiac cells does not influence EV concentration but strongly regulates the EV cargo and affects migration. This might indicate a role for EV-mediated communication in isoflurane- and hypoxia-induced in vitro preconditioning.

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Reduced expression of let‐7f activates TGF‐β/ALK5 pathway and leads to impaired ischaemia‐induced neovascularization after cigarette smoke exposure

Cited by 26 publications

References 46 publications

LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d

LncRNA PFL contributes to cardiac fibrosis by acting as a competing endogenous RNA of let-7d

MicroRNA expression profile of human advanced coronary atherosclerotic plaques

Characterization of extracellular vesicles derived from cardiac cells in an in vitro model of preconditioning

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