Cardiomyocyte‐specific Peli1 contributes to the pressure overload‐induced cardiac fibrosis through miR ‐494‐3p‐dependent exosomal communication

Abstract

Cardiac fibrosis is an essential pathological process in pressure overload (PO)induced heart failure. Recently, myocyte-fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs-containing exosomes (Exos). Peli1 regulates the activation of NF-κB and AP-1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNAmediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM-conditional deletion of Peli1 improved PO-induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)-induced WT CMs (WT MS-Exos) promote activation of CFs, Peli1 −/− MS-Exos reversed it. Furthermore, miRNA microarray and qPCR analysis showed that miR-494-3p was increased in WT MS-Exos while being down regulated in Peli1 −/− MS-Exos. Mechanistically, Peli1 promoted miR-494-3p

Mechanical overload-induced release of extracellular mitochondrial particles from tendon cells leads to inflammation in tendinopathy

“…This work represents the first demonstration of ExtraMito particles functioning as an intercellular crosstalk signal in mechanobiology. While our conclusions were drawn based on tendinopathy, these findings may extend to other diseases induced by mechanical overload, such as pressure overload-induced cardiac fibrosis and heart failure 63 and ocular hypertension-caused glaucoma 64 , as inflammation has been found to be an essential associated event in these overload-induced diseases 65 , 66 .…”

The Roles of Exosome-Derived microRNAs in Cardiac Fibrosis

“…Previous studies [ 106 ] have established that miRNAs from cardiomyocytes regulate Pellino1 (Peli1)-mediated NF-κB and AP-1 activation. In an extension of this work, Tang et al [ 74 ] discovered that the absence of Peli1 in cardiomyocyte-derived exosomes mitigates pressure overload and mechanical stretch-induced cardiac fibrosis. Through miRNA microarray analysis and qPCR of exosomes released by cardiomyocytes, the researchers identified miR-494-3p as a downstream target of Peli1.…”

Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers

“…Moreover, Peli1 mediates the K63-Ub of cIAP2, activating JNK and P38 by via increasing cIAP2-mediated TRAFT3 degradation ( 26 , 80 ). Peli1 induces miR-494-3p expression in cardiomyocyte exosomes, inhibiting its target, phosphatase and tensin homolog (PTEN), and activating the AKT, Smad2/3, and extracellular signal-regulated kinase (ERK) signaling pathways ( 100 ). Peli1 activates the MAPK pathway by modulating endoplasmic reticulum (ER) stress.…”

“…Peli1 activates the AKT pathway and is involved in various biological and pathological processes, including cancer progression ( 23 , 103 ), drug resistance ( 104 ), angiogenesis ( 96 , 100 , 105 ), T follicular helper (Tfh) cell differentiation ( 93 ), microglia activation ( 98 ), glycolysis, and macrophage M1 polarization ( 31 ). Peli1 regulates AKT activationvia several pathways: 1) Peli1 inhibits the inducible co-stimulator (ICOS) and suppresses the PI3K/AKT pathway downstream of ICOS by mediating ubiquitination-dependent c-Rel degradation ( 93 ); 2) Peli1 upregulates miR-494-3p expression in cardiomyocyte exosomes and inhibits its target PTEN.…”

“…Peli1 regulates AKT activationvia several pathways: 1) Peli1 inhibits the inducible co-stimulator (ICOS) and suppresses the PI3K/AKT pathway downstream of ICOS by mediating ubiquitination-dependent c-Rel degradation ( 93 ); 2) Peli1 upregulates miR-494-3p expression in cardiomyocyte exosomes and inhibits its target PTEN. This inhibition prevents PTEN-mediated phosphatidylinositol 3,4,5-trisphosphate (PIP3) dephosphorylation, activating downstream AKT/endothelial nitric oxide synthase/nitric oxide signaling ( 100 ).…”