MicroRNA-27b-3p down-regulates FGF1 and aggravates pathological cardiac remodelling

Abstract

Aims The heart undergoes pathological remodelling under increased stress and neuronal imbalance. MicroRNAs (miRNAs) are involved in post-transcriptional regulation of genes in cardiac physiology and pathology. However, the mechanisms underlying miRNA-mediated regulation of pathological cardiac remodelling remain to be studied. This study aimed to explore the function of endogenous microRNA-27b-3p (miR-27b-3p) in pathological cardiac remodelling. Methods and results miR-27b-3p expression was elevated in the heart of a transverse aortic constriction (TAC)-induced cardiac hypertrophy mouse model. MiR-27b-knockout mice showed significantly attenuated cardiac hypertrophy, fibrosis, and inflammation induced by two independent pathological cardiac hypertrophy models, TAC and Angiotensin II (Ang II) perfusion. Transcriptome sequencing analysis revealed that miR-27b deletion significantly downregulated TAC-induced cardiac hypertrophy, fibrosis, and inflammatory genes. We identified fibroblast growth factor 1 (FGF1) as a miR-27b-3p target gene in the heart and was upregulated in miR-27b-null mice. We found that both recombinant FGF1 (rFGF1) and inhibition of miR-27b-3p enhanced mitochondrial oxidative phosphorylation (OXPHOS) and inhibited cardiomyocyte hypertrophy. Importantly, rFGF1 administration inhibited cardiac hypertrophy and fibrosis in TAC or Ang II-induced models, and enhanced OXPHOS by activating PGC1α/β. Conclusions Our study demonstrated that miR-27b-3p induces pathological cardiac remodelling and suggests that inhibition of endogenous miR-27b-3p or administration of FGF1 might have the potential to suppress cardiac remodelling in a clinical setting. Translational perspective MicroRNAs (miRNAs) are involved in post-transcriptional regulation of genes in cardiac physiology and pathology. However, the mechanisms underlying miRNA-mediated regulation of pathological cardiac remodelling remain to be studied. We show for the first time that miR-27b deletion attenuates cardiac hypertrophy, fibrosis, and inflammation and that rFGF1 administration inhibits cardiac hypertrophy and fibrosis in TAC- or Ang II-induced models, and enhances OXPHOS by activating PGC1α/β. Our findings suggest that miR-27b-3p and FGF1 may be potential therapeutic targets to treat conditions characterised by pathological cardiac remodelling.

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy

“…In addition, miRs also appear to be effective during hypertrophic response. The latest research progress by Li's group suggested that miR-27b-3p deficiency remarkably reduced cardiac hypertrophy, fibrosis, and inflammation in both TAC and Angiotensin II (Ang II) perfusion-induced murine models; surprisingly, inhibition of endogenous miR-27b-3p could significantly enhance mitochondrial oxidative phosphorylation (OXPHOS) through activating PGC1α/β ( 65 ). Overexpression of miR-142-3p reversed MMP, mitochondrial density and effectively abolished hypertrophic response in CMs stimulated by Ang II, which was obtained by suppressing the expression of SH2B1 ( 66 ).…”

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction

“…Pro-fibrotic miRNAs promote the increased expression of ECM components and other fibrosis-related proteins in different tissues, and therefore, could serve as an attractive target for therapeutic modifications in cardiac diseases such as MI, atrial fibrillation, cardiac ischemia, and others [ 79 , 80 , 81 , 82 ]. One of the first examples to be considered was miR-27b, which has been shown to stimulate hypertrophy and promote heart failure, whereas its inhibition alleviates cardiac dysfunction [ 83 , 84 ]. Further findings have indicated that a TGF-β1/Smad signaling pathway plays a key role in the regulation of miR-27b, since TGF-β1 interfered with the activity of the miR-27b promoter and reduced the growth of hypertrophic cells, while smad4 knockout, in contrast, stimulated hypertrophy [ 85 ].…”

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

“…The miR-21 in macrophages also regulates macrophage–fibroblast communication and promotes activation of quiescent fibroblasts into myofibroblasts, promoting cardiac fibrosis [ 133 ]. MiR-27b-3p suppresses mitochondrial oxidative phosphorylation (OXPHOS) through the target gene FGF1, and inhibition of FGF1 alleviates TAC or Ang-II-induced cardiac fibrosis by enhancing OXPHOS [ 134 ]. In addition, miRNAs such as miR-590-3p [ 135 ], miR-221/222 [ 136 ], and miR-1954 [ 137 ] alleviate cardiac fibrosis by regulating ZEB1, Smad2, and THBS1.…”