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.
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%).
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: email@example.com).
Received March 25, 2011
Accepted June 21, 2011