Circ-sh3rf3/GATA-4/miR-29a regulatory axis in fibroblast–myofibroblast differentiation and myocardial fibrosis

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression

“…CircHIPK3 attenuates heart aging by promoting the binding of E3 ubiquitin ligase β-TrCP to HuR, enhancing ubiquitination and degradation of HuR and ultimately decreasing the activity of p21 in mice in vivo and in vitro ( 70 ). Additionally, it was verified that circ-sh3rf3 inhibited fibroblast-to-myofibroblast differentiation and consequently alleviated myocardial fibrosis by directly enhancing GATA-4 ubiquitination degradation via the E3 ubiquitin–protein ligase sh3rf3 and then abolishing GATA-4 inhibition of miR-29a expression ( 71 ). Furthermore, loss of miR-483 contributes to endothelial inflammation and consequently calcific AV disease and exerts deteriorating effects by increasing the expression of Ube2c, enhancing ubiquitination-induced pVHL degradation and activating the HIF-1α pathway ( 72 ).…”

“…This is particularly noteworthy that circRNA, as an emerging ncRNA, has received much attention in recent years. The mechanism is that circRNAs are involved in CVD progression by sponging miRNAs and regulating downstream proteins (circRNA/miRNA/ubiquitin ligase or deubiquitinating enzymes/protein axis) via ubiquitination, for example, circDLGAP4/miR-143/HECTD1 axis improved stroke ( 89 ), circ-UBR4/miR-637/FOXO4, circ-UBR4/miR-107/ROCK1, circ-UBR4/miR-491-5p/NRP2, circ-UBR4/miR-185-5p/FRS2, and circ-CHFR/miR-214-3p/PAPPA axes as well as inhibition of circ_USP36/miR-197-3p/ROBO1 axis could ameliorate atherosclerosis ( 75 – 81 ), circ-HECTD1/miR-133b/TRAF3 and circ_HECTD1/miR-27a-3p/FSTL1 axes as well as inhibition of circNfix/Nedd4l/Ybx1 and circNfix/miR-214/Gsk3β axes could reduce myocardial infarction and CVD ( 49 , 94 , 95 ), circ-sh3rf3/sh3rf3/GATA-4/miR-29a alleviated cardiac fibrosis ( 71 ).…”

“…Similarly, miR-124 and REST provide therapeutic benefits in protecting against stroke via miR-124/USP14/REST, while other studies have demonstrated that lithium or M2 microglia-derived exosomes can regulate miR-124 and REST to play a neuroprotective role ( 86 , 87 , 102 ). Cardiomyocyte hypertrophy and myocardial fibrosis can be treated via the regulation of the miR-485-5p/MAPL/Mfn2 axis and Circ-sh3rf3/GATA-4/miR-29a cascade ( 58 , 71 ). Moreover, five notable crosstalk pathways, circ-UBR4/miR-637/FOXO4, circ-UBR4/miR-107/ROCK1, circ-UBR4/miR-491-5p/NRP2, circ-UBR4/miR-185-5p/FRS2 and circ-CHFR/miR-214-3p/PAPPA axis, regulate VSMC migration and growth to improve atherosclerosis ( 75 , 77 – 80 ).…”

Circular RNA: A new expectation for cardiovascular diseases

“…Circ-sh3rf3 sponges GATA-4 protein to inhibit its expression and eliminate the inhibitory effect of GATA-4 on miR-29a, thereby upregulating miR-29a expression and thereby inhibiting fibroblast-myofibroblast differentiation and cardiac fibrosis. 94 By acting as a scaffold, circYap, which inhibits myocardial fibrosis and protects cardiac pumping function, binds directly to tropomyosin-4 (TMP4) and gamma-actin (ACTG) and makes the interaction between the two proteins more stable, in consequence increasing the inhibition of actin polymerization and subsequent fibrosis. 95 CircHelz, when upregulated by transcriptional activators, can bind to YAP1 and promote its localization in the nucleus, leading to myocardial fibrosis, and therefore myocardial fibrosis can be treated by knocking out circHelz knockdown to inhibit nuclear translocation of YAP1.…”

“…Circ‐sh3rf3 sponges GATA‐4 protein to inhibit its expression and eliminate the inhibitory effect of GATA‐4 on miR‐29a, thereby upregulating miR‐29a expression and thereby inhibiting fibroblast‐myofibroblast differentiation and cardiac fibrosis 94 . By acting as a scaffold, circYap, which inhibits myocardial fibrosis and protects cardiac pumping function, binds directly to tropomyosin‐4 (TMP4) and gamma‐actin (ACTG) and makes the interaction between the two proteins more stable, in consequence increasing the inhibition of actin polymerization and subsequent fibrosis 95 .…”