Deficiency of miR-1954 promotes cardiac fibrosis

Abstract

Cardiac remodeling due to hemodynamic overload is associated with significant morbidity and mortality. In response to stress, cardiomyocyte (CM) become hypertrophied whereas cardiac fibroblasts convert into myofibroblasts. The phenomenon leads to the development of cardiac hypertrophy, fibrosis and impair cardiac function. Previously, we have shown the pivotal role of miRNA (a new class of post-transcriptional regulators) in cardiac remodeling, but, loss of miRNA contributing the onset of cardiac remodeling remains elusive. Using next generation miRNA sequencing, we discovered a panel of novel dysregulated miRNAs from read-data, secondary structure and miRPara classification score analyses in wild-type mice (WT) infused with Angiotensin II (Ang-II). Among them, one was identified as miR-1954, a novel miRNA which was significantly reduced in Ang II-infusion. Following an unbiased approach, we confirmed that Sp1-Gata4-Col I-Tsp1-axis is the bona-fide targets. Our hypothesis is that deficiency of miR-1954 exacerbates cardiac remodeling leading to hypertrophy and fibrosis and overexpression of miR-1954 mitigates the cardiac damage and abrogates remodeling by modulating Sp1-Gata4-Col I-Tsp1-axis. Data demonstrated that depletion of miR-1954 in CM triggers hypertrophic response by modulating Sp1 and Gata4; releases soluble factors (Tgfb1) that triggers cardiac fibroblasts proliferation; upregulation of thrombospondin 1 (Tsp1) and collagen I (Col I). Overexpression of miR-1954 in CM reverses the process implicated a cellular cross-talk. Cardiac-specific overexpression of pre-miR-1954 transgenic mice (miR-1954 Tg) showed reduced cardiac mass and improved function compared to WT littermate after Ang-II treatment. Along the line, data showed significant reduction of hypertrophy marker genes, fibrotic genes, inflammatory genes and restoration of SERCA2. Inhibition of miR-1954 by locked nucleic acid of anti-miR-1954 exacerbates cardiac hypertrophy and fibrosis. Our findings provide evidence that loss of miR-1954 promotes cardiac remodeling and overexpression of miR-1954 reverses the process. We conclude that miR-1954 is a critical regulator in cardiac remodeling and may be useful for therapeutic benefit.