91 Overlapping effects of MI-R-21 inhibition and oral anti-fibrotic and anti-inflammatory drugs: rationale for drug repurposing to relieve ischemia/reperfusion injury

Abstract

Abstract Aims Reperfusion strategies have reduced the mortality of ST-segment elevation myocardial infarction (STEMI), but ischemia/reperfusion (I/R) injury still represents an important issue, and the prevalence of heart failure (HF) after STEMI is raising. Intracoronary infusion of miR-21 inhibitors after reperfusion has been reported to reduce cardiac fibrosis and hypertrophy and improve cardiac function in pigs. Possible drawbacks of miR-21 inhibitors are their high costs and the need for intracoronary administration. Oral drugs with anti-fibrotic or anti-inflammatory actions could have similar effects on protein expression than miR-21 inhibition. We examined the 2 drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone) and colchicine, which is being evaluated for the prevention of adverse ventricular remodelling after STEMI (NCT03156816). Methods and results We identified the regulatory profile of miR-21 (588 target genes). Only 99 of these interactions were supported by robust experimental data (i.e., information from reporter gene assays), and were then considered for further examination. The biological significance of these 99 targets was evaluated through over-representation analysis, and 13 genes were identified as potentially related to cardiovascular diseases. We retrieved all known targets and main downstream interactions of nintedanib, pirfenidone and colchicine (source: www.drugbank.ca). We cross-validated these datasets by using neural network analyses to search for protein-protein interactions, focusing on those shared by miR-21 inhibition and each one of the 3 drugs. Nintedanib and miR-21 inhibition shared many targets, which could indicate overlapping mechanisms of action. The proto-oncogene SRC, which participates in gene transcription, immune response, apoptosis and migration, emerged as the leading signaling effector. By blocking SRC expression and many downstream effectors of SRC, as well as platelet derived growth factor, nintedanib could decreased miR-21 expression. The molecular effects of nintedanib include an inhibition of inflammation, fibrosis and angiogenesis, and then ultimately a relief from I/R injury, in a similar fashion than anti-miR-21. Contrary to nintedanib, no overlap between the effects of pirfenidone and miR-21 inhibition was found. Conversely, colchicine seems to determine an indirect blockade of the important pro-inflammatory signaling pathway AKT/NFKB, similarly to miR-21 inhibition. Colchicine has also been proposed to inhibit SRC, but few published data are available. Conclusion miR-21 inhibition is emerging as a potential treatment for I/R cardiac injury, but its applicability in clinical practice is burdened by several limitations. Drug repurposing could aid this situation by mimicking the molecular activity of miR-21 inhibition. Through a bioinformatic approach, we found that nintedanib could exert beneficial effects similar to those reported for miR-21 inhibition, with a lower degree of overlap between the effects of colchicine and anti-miR-21. If confirmed by experimental evidence, nintedanib or colchicine could enter the stage of clinical trials to assess their efficacy as cardioprotective therapies in human patients with STEMI.