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Posttranscriptional Regulation of the 2-Subunit of Cardiac L-type Ca2+ Channels by MicroRNAs During Long-term Exposure to Isoproterenol in Rats

Carrillo, Elba D. PhD; Escobar, Yesenia MS; González, German MS; Hernández, Ascención BS; Galindo, José M. BS; García, María C. PhD; Sánchez, Jorge A. PhD

Journal of Cardiovascular Pharmacology: November 2011 - Volume 58 - Issue 5 - p 470–478
doi: 10.1097/FJC.0b013e31822a789b
Original Article

Introduction and Methods: The effects of long-term β-adrenergic administration on the expression levels of the cardiac L-type Ca2+ channel β2 subunit, which regulates channel trafficking and function, were characterized in adult rats.

Results: Systemic administration of isoproterenol (150 mg·kg·h−1) for 2 d led to a 50% increase in the ventricular wet weight-to-body weight ratio (mg/g) and of more than two-fold in the expression of actin protein. In contrast, β2 subunit protein levels decreased (down to 49%), while mRNA levels remained unchanged. Furthermore, levels of microRNAs (miRs), including miR-21 and miR-132, were upregulated (7.2 and 7.9 fold, respectively). Transfection of these miRs into HEK293 cells attenuated expression of a luciferase reporter gene controlled by a conserved 3′-untranslated region (UTR) of the β2 subunit (down to 67% and 56%, respectively). Systemic administration of isoproterenol also led to briefer intracellular Ca2+ transients during action potentials measured in isolated cardiomyocytes (down to 65%).

Conclusion: These results suggest that cardiac L-type Ca2+ channel β2 subunit protein expression may be downregulated by miRs in response to long-term activation of β-adrenergic signaling, possibly as an adaptive response in cardiac hypertrophy and sustained β-adrenergic states.

Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados, del Instituto Politécnico Nacional, México, DF, México.

Supported in part by CONACYT, Mexico (grant numbers: 60880 and 102100). Y. Escobar and G. González were supported by fellowships from CONACYT, Mexico.

The authors report no conflict of interest.

Reprints: Jorge A. Sánchez, PhD, Departamento de Farmacología, Centro de Investigación y Estudios Avanzados del Instituto Poltécnico Nacional, Av. Politécnico 2508. San Pedro Zacatenco, México, D.F. 07360 (e-mail: dr_jorge_sanchez@hotmail.com).

Received March 25, 2011

Accepted June 21, 2011

© 2011 Lippincott Williams & Wilkins, Inc.