miRNAs at the heart of the matter

Abstract

Cardiovascular disease is among the main causes of morbidity and mortality in developed countries. The pathological process of the heart is associated with altered expression profile of genes that are important for cardiac function. MicroRNAs (miRNAs) have emerged as one of the central players of gene expression regulation. The implications of miRNAs in the pathological process of cardiovascular system have recently been recognized, representing the most rapidly evolving research field. Here, we summarize and analyze the currently available data from our own laboratory and other groups, providing a comprehensive overview of miRNA function in the heart, including a brief introduction of miRNA biology, expression profile of miRNAs in cardiac tissue, role of miRNAs in cardiac hypertrophy and heart failure, the arrhythmogenic potential of miRNAs, the involvement of miRNAs in vascular angiogenesis, and regulation of cardiomyocyte apoptosis by miRNAs. The target genes and signaling pathways linking the miRNAs to cardiovascular disease are highlighted. The applications of miRNA interference technologies for manipulating miRNA expression, stability, and function as new strategies for molecular therapy of human disease are evaluated. Finally, some specific issues related to future directions of the research on miRNAs relevant to cardiovascular disease are pinpointed and speculated.

Fig. 1

Diagram depicting the miRNAs, along with their target genes, which have been experimentally evidenced for their participation in the development of cardiac hypertrophy. THRAP1 thyroid hormone receptor associated protein 1; RasGAP Ras GTPase-activating protein; Cdk9 cyclin-dependent kinase 9; Rheb Ras homolog enriched in brain; RhoA, a GDP–GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. These proteins have been implicated in hypertrophy

Fig. 2

Schematic illustration of the role of the muscle-specific miRNAs miR-1 and miR-133 in arrhythmias. Cx43 connexin-43; IK1 inward rectifier K+ current; IKr rapid delayed rectifier K+ current; IKs slow delayed rectifier K+ current; If pacemaker nonselective cation current or funny current; Kir2.1 a pore-forming K+ channel α-subunit for IK1; HERG a pore-forming K+ channel α-subunit for IKr; KCNQ1 a pore-forming K+ channel α-subunit for IKs; KCNE1 an auxiliary β-subunit for IKs; HCN2 and HCN4 α-subunits for If; APD action potential duration; ERP effective refractory period; EAD early after depolarization

Fig. 3

Upper panel: Schematic presentation of actions of miRNA-masking antisense oligonucleotide (miR-Mask) compared with the conventional antisense oligodeoxynucleotide (ODN) and antimiRNA antisense inhibitor oligonucleotide (AMO) technologies. Synthetic nucleic acids are introduced into the cells. Antisense ODNs bind to the coding region of the target mRNA and hinder the translation process; AMOs bind to the target miRNA, resulting in miRNA cleavage; miR-Masks bind to the binding site of miRNAs in 3′UTR of the target mRNA and prevent miRNAs from binding to the target mRNA, leading to a relief of translational repression without affecting miRNAs. Lower panel: Schematic presentation of actions of miRNA mimic (miR-Mimic) compared with the miRNA and small interference RNA (siRNA). Synthetic miR-Mimic and siRNA are introduced into the cells and endogenous miRNA is synthesized by the cell. siRNAs bind to the coding region of target miRNAs and cause mRNA cleavage; miRNAs bind to 3′UTR of multiple target mRNAs and produce non-gene-specific posttranscriptional repression to inhibit translation; miR-Mimics bind to 3′UTR of unique target mRNAs and produce gene-specific posttranscriptional repression to inhibit translation