Histological section of mouse heart (stained for Masson's trichrome). Credit: Science

How microRNAs (miRNAs) influence heart development and disease is a topic of growing interest. miRNAs regulate gene expression post-transcriptionally, typically by binding to mRNAs and inhibiting their translation. Three recent papers show that miRNAs are essential for heart development and function, regulating the expression of genes involved in electrical conductance, hypertrophy and contractility.

In mice with deletion of the muscle-specific miRNA miR-1-2, Zhao et al. observed a range of heart abnormalities (Cell 129, 1–15). Some embryos died from heart structure defects, whereas surviving adults had electrical conduction defects and, unusually, mitotically active cardiomyocytes. The researchers identified several potential miR-1-2 target mRNAs, including Irx5, which they showed is a direct target of miR-1-2. Since Irx5 encodes a homeobox transcription factor known to regulate cardiac repolarization, it may be the culprit for the electrical conduction defect seen in adult mice.

Muscle-specific miRNAs also regulate hypertrophic growth of heart muscle, report Carè et al. in this issue of Nature Medicine (13, 613–618). The researchers showed that expression of miR-1 and another muscle-specific miRNA, miR-133, is decreased in human and mouse hypertrophic heart tissue. In functional studies, the researchers showed that both miRNAs block cardiomyocyte hypertrophy. Most notably, suppression of miR-133 expression in mice using an oligonucleotide “antagomir” resulted in cardiac hypertrophy. In search of a molecular mechanism for how miR-133 controls heart size, the researchers showed that the transcripts of Rhoa, Cdc42 and Whsc2 are direct targets of this miRNA.

In the third study, Van Rooj et al. showed that the muscle-specific miR-208 controls expression of the β-MHC gene, a regulator of cardiac contractility (Science, doi: 10.1126/science.1139089). Mice with miR-208 deleted developed slight defects in heart function as they aged. More strikingly, these mice failed to undergo cardiac hypertrophy under inducing conditions, and β-MHC expression was not upregulated as expected during the hypertrophic response. Repression of β-MHC expression by the thyroid hormone receptor is important for regulating cardiac contractility. The researchers showed that miR-208 targets THRAP1, a regulator of the thyroid hormone receptor, suggesting a regulatory circuit by which miR-208 controls β-MHC expression.

From these and other recent papers, it seems clear that miRNAs have a pivotal role in regulating gene expression in the heart. Unraveling the regulatory circuits involved may be challenging, given that a single miRNA can regulate the expression of many mRNA targets. As important regulators of heart function, miRNAs may represent attractive targets for treating heart disease.