MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets

Abstract

MicroRNAs act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies have revealed key roles of microRNAs as regulators of the growth, development, function, and stress responsiveness of the heart, providing glimpses of undiscovered regulatory mechanisms and potential therapeutic targets for the treatment of heart disease.

Figure 1. miRNA biogenesis and function.

The primary transcripts of miRNAs, called pri-miRNAs, are transcribed as individual miRNA genes, from introns of protein-coding genes, or from polycistronic transcripts. The RNase Drosha further processes the pri-miRNA into 70–100 nucleotide, hairpin-shaped precursors, called pre-miRNA, which are exported from the nucleus by exportin 5. In the cytoplasm, the pre-miRNA is cleaved by Dicer into an miRNA:miRNA* duplex. Assembled into the RISC, the mature miRNA negatively regulates gene expression by either translational repression or mRNA degradation, which is dependent on sequence complementarity between the miRNA and the target mRNA. ORF, open reading frame.

Figure 2. Induction of cardiac hypertrophy and heart failure by miR-195.

H&E sections of 2-week-old wild-type and transgenic mice expressing miR-195 under control of the αMHC promoter. In transgenic as compared with wild-type mice, moderate levels of miR-195 expression (26-fold) cause cardiac hypertrophy, and higher levels of expression (29-fold) cause dilated cardiomyopathy with ventricular dilatation and wall thinning. Reproduced with permission from Proceedings of the National Academy of Sciences of the United States of America (8). Scale bar: 2 mm.

Figure 3. Roles of specific miRNAs in cardiac hypertrophy.

Stress signals drive a pathological remodeling response of the adult heart, which is characterized by hypertrophy, ventricular dilatation, and fibrosis. miR-208 is required for stress-dependent remodeling and miR-195, which is induced by cardiac stress, is sufficient to drive cardiac remodeling. miR-133 appears to play a negative role in cardiac hypertrophy (5, 6, 8).

Figure 4. Requirement of miR-208 for cardiomyocyte hypertrophy and fibrosis.

(A) Schematic diagram of a heart following thoracic aortic banding (TAB). (B) Sections of hearts of approximately 3-month-old wild-type and miR-208^–/– mice are shown following sham operation or TAB for 21 days. High-magnification views of the ventricular wall are shown at the bottom. Trichrome staining identifies fibrosis in blue. Note that hypertrophy and fibrosis are diminished in miR208^–/– mice compared with wild-type following TAB. Scale bars: 2 mm (top); 20 μm (bottom). Reproduced with permission from Science (5).

Figure 5. A model for the mechanism of action of miR-208.

αMHC and βMHC promote fast and slow contractility, respectively. TRs act through positive and negative TREs to activate and repress expression of the αMHC and βMHC genes, respectively, which are linked. Propylthiouracil (PTU) prevents T3 biosynthesis, resulting in hypothyroidism and upregulation of βMHC due to loss of the repressive action of the TR on the negative TRE. Stress signals also activate βMHC expression, at least in part through the TR. Developmental signals drive βMHC expression before birth through separate regulatory elements. miR-208, encoded by the αMHC gene, negatively regulates mRNA targets encoding THRAP1 and other negative regulators of βMHC expression. miR-208 also represses an activator of fast skeletal muscle genes. Modified with permission from Science (5).