MicroRNA-133 Modulates the β ₁ -Adrenergic Receptor Transduction Cascade

Abstract

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, β 1 -adrenergic receptor (β 1 AR) and other components of the β 1 AR 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 β 1 AR 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 β 1 AR 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 β 1 AR transduction cascade and is cardioprotective during heart failure.

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

“…15,17 More recently, microRNA-133, a potent regulator of cardiac hypertrophy was shown to directly target EPAC mRNA and several other components of the cAMP signaling cascade, including the β1-AR and the catalytic subunit β of PKA. 127 In vitro data demonstrated the involvement of EPAC in cardiomyocyte growth. 103 Direct activation of endogenous EPAC with 8-CPT or overexpression of EPAC1, the major EPAC isoform in rat cardiac myocytes, increased various markers of hypertrophy, such as cell-surface area, protein synthesis, and atrial natriuretic factor expression.…”

Long Noncoding RNAs and MicroRNAs in Cardiovascular Pathophysiology

“…25 miR-133 modulates inotropism by regulating the expression of multiple components of the β1-adrenergic pathway, including the receptor itself. 26 In addition to relatively abundant cardiac microRNAs, many microRNAs are expressed at relatively low levels under basal conditions and during pathological stress are strongly upregulated, becoming, thus, functionally important during disease. An example is the brain-enriched microRNA miR-212/132 family, which becomes activated during HF in humans 27 and animal models.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…MiR133 directly targets adenylate cyclase VI and the catalytic subunit of PKA, both elements of the β1AR signal transduction cascade, reducing signalling [17] . Similarly carvedilol, an in vivo βadrenergic blocker, improves the cardiac function in infarcted rats by restoring miR133 expression, resulting in reduced cardiomyocyte apoptosis [18] .…”