Molecular mechanism of diabetic cardiomyopathy and modulation of microRNA function by synthetic oligonucleotides

Abstract

Diabetic cardiomyopathy (DCM) is a chronic complication in individuals with diabetes and is characterized by ventricular dilation and hypertrophy, diastolic dysfunction, decreased or preserved systolic function and reduced ejection fraction eventually resulting in heart failure. Despite being well characterized, the fundamental mechanisms leading to DCM are still elusive. Recent studies identified the involvement of small non-coding small RNA molecules such as microRNAs (miRs) playing a key role in the etiology of DCM. Therefore, miRs associated with DCM represents a new class of targets for the development of mechanistic therapeutics, which may yield marked benefits compared to other therapeutic approaches. Indeed, few miRs currently under active clinical investigation, with many expressing cautious optimism that miRs based therapies will succeed in the coming years. The major caution in using miRs based therapy is the need to improve the stability and specificity following systemic injection, which can be achieved through chemical and structural modification. In this review, we first discuss the established role of miRs in DCM and the advances in miRs based therapeutic strategies for the prevention/treatment of DCM. We next discuss the currently employed chemical modification of miR oligonucleotides and their utility in therapies specifically focusing on the DCM. Finally, we summarize the commonly used delivery system and approaches for assessment of miRNA modulation and potential off-target effects.

Keywords: Clinical application of microRNA; Delivery of therapeutic microRNA; Diabetic cardiomyopathy; MicroRNA; Modulation of microRNA.

Fig. 1

Mechanisms involved in the pathophysiology of diabetic cardiomyopathy. Schematic representation of the multiple potential mechanisms that have been implicated in the pathophysiology of diabetic cardiomyopathy. The steady increase in reports presenting novel mechanistic data on this subject expands the list of potential underlying mechanisms

Fig. 2

Biogenesis of miRNA. Canonical pathway of miR biogenesis in which miRs are transcribed by RNA polymerase II from intergenic, intronic, or polycistronic loci to long primary transcript, called primary miR (pri-miRNA), which consists in a stem, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. Microprocessor complex (Drosha and DGCR8 cofactor) cleaves the stem-loop and releases a small hairpin-shaped RNA, called precursor miRNA (pre-miRNA). Following, pre-miRNA is exported into the cytoplasm by the transport complex formed by protein Exportin 5, pre-miRNAs are cleaved by a ternary complex formed by Dicer, producing small RNA duplexes (miR–miR). Next, these are loaded onto an Argonaute 2 protein (AGO2) to form an immature RNA-induced silencing complex (RISC) or pre-RISC. AGO protein separates the two strands to generate a mature RISC effector. Finally, RISC binds the target mRNA through complementary binding of 6–8 base pairs of the miR, with a specific sequence of the target resulting in the gene silencing

Fig. 3

Chemical modifications of miRNA oligonucleotides. Structures of chemically modification. a Structures of the most commonly used chemical modifications in oligonucleotide chemistry; locked nucleic acid (LNA) is a bicyclic RNA analogue in which the ribose is locked in a C3′-endo conformation by introduction of a 2′-O,4′-C methylene bridge, b the nonbridging phosphate atom is replaced with a sulfur atom to give a phosphorothioate (PS) modification, c six-membered morpholine ring replaces the sugar moiety in morpholino oligomers. d In the ribose 2′-OH group modification: the 2′-OH group is modified with 2′-O-methyl (2′-O-Me), e 2′-OH group is modified with 2′-fluoro (2′-F), f 2′-OH group is modified with 2′-O-methoxyethyl (2′-MOE)

Fig. 4

Isomeric configuration phosphorothioate modification. Formation of diastereomers by phosphorothioate (PS) backbone modifications. a, b Chiral arrangements of Sp and Rp diastereomers. c, d Formation of 3′-phosphorothioate and 5′-phosphorothioate inter-nucleotide linkage from Sp and Rp diastereomers