Highlights d Conditional PDGFR-b activation in cardiomyocytes promotes heart regeneration d EZH2 is required in PDGFR-b-induced cardiomyocyte proliferation d PDGFR-b regulates EZH2 expression via the PI3K/p-Akt pathway d AAV9-mediated PDGFR-b activation improves adult cardiac repair and systolic function
Background: Lysophosphatidic acid (LPA), a bioactive phospholipid released by activated platelets, can induce platelet shape changes and aggregation, which may play an important role in thrombosis. In contrast, the interaction of LPA with neutrophils in thrombosis has not been studied. Recently, neutrophil extracellular traps (NETs) have been shown to bind plasma proteins and activate platelets, which promotes thrombosis.Objectives: To investigate whether LPA could activate neutrophils to release NETs, predisposing to thrombosis and promoting thrombus stability.Methods: Levels of neutrophils, NETs, and LPA were detected in 56 participants.Immunofluorescence of NETs and autotaxin, the LPA-producing ectoenzyme, were performed. Induction of NETs and signaling pathways were explored in vitro.Results: Patients with acute pulmonary embolism showed elevated levels of neutrophils, NETs (dsDNA, MPO-DNA, citrullinated histone H3, and nucleosomes), LPA18:1, and LPA20:4. NETs were present in human intrapulmonary thrombi and were surrounded by autotaxin. LPA18:1 induced rapid release of NETs from human neutrophils via a peptidylarginine deiminase 4-dependent pathway. LPA-induced NETs provided a scaffolding for plasma protein binding and generated a tissue plasminogen | 1953 LI et aL.
Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (
Cfast
), which is significantly elevated after MI. Silencing
Cfast
expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of
Cfast
by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of
Cfast
ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the
Cfast
interacting proteins. Mechanistically,
Cfast
competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies
Cfast
as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress.
Cfast
could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.
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