MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade

Circ Res. 2014 Jul 7;115(2):273-83. doi: 10.1161/CIRCRESAHA.115.303252. Epub 2014 May 7.


Rationale: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability.

Objective: To determine whether miR-133 affects β-adrenergic receptor signaling during progression to heart failure.

Methods and results: Based on bioinformatic analysis, β1-adrenergic receptor (β1AR) and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective β1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice.

Conclusions: miR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.

Keywords: adrenergic beta-1 receptor antagonists; cyclic AMP; heart failure; microRNAs; myocytes, cardiac.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / physiology
  • Adenylyl Cyclases / physiology
  • Animals
  • Apoptosis
  • Cells, Cultured
  • Cyclic AMP / physiology*
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Disease Progression
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Guanine Nucleotide Exchange Factors / physiology
  • Male
  • Metoprolol / pharmacology
  • Metoprolol / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta-1 / physiology*
  • Recombinant Fusion Proteins / genetics
  • Second Messenger Systems / physiology*


  • 3' Untranslated Regions
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • MicroRNAs
  • Mirn133 microRNA, mouse
  • RNA, Messenger
  • Receptors, Adrenergic, beta-1
  • Recombinant Fusion Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Adenylyl Cyclases
  • adenylyl cyclase 6
  • Metoprolol