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Am J Physiol Heart Circ Physiol 296: H728-H734, 2009. First published January 16, 2009; doi:10.1152/ajpheart.00584.2008
0363-6135/09 $8.00
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Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxin-sensitive Gi protein and cAMP

Randa Hilal-Dandan, Huaping He, Jody L. Martin, Laurence L. Brunton, and Wolfgang H. Dillmann

Departments of Pharmacology and Medicine, University of California, San Diego, La Jolla, California

Submitted 4 June 2008 ; accepted in final form 3 January 2009

Downregulation of the sarcoplasmic reticulum calcium ATPase (SERCA2) is associated with diastolic dysfunction in the failing heart. Elevated plasma endothelin-1 (ET) levels are correlated with congestive heart failure suggesting that ET may play a pathophysiological role. We have investigated the ability of ET to regulate SERCA2 gene expression in isolated adult rat ventricular myocytes. We find that ET enhances net protein synthesis by ~40% but significantly downregulates SERCA2 mRNA expression, time dependently, by ~30–50%, and the expression of SERCA2 protein by ~ 50%. In myoyctes, ET binds to ETA receptor that couples to Gq and Gi proteins. Inhibition of Gq-PLC-induced phosphoinositide (PI) hydrolysis with U73122 [GenBank] (1 µM) or inhibition of Gi protein with pertussis toxin (PTX) abolishes the ability of ET to downregulate SERCA2 mRNA gene expression. Further investigation suggests that ET coupling to PTX-sensitive Gi with consequent lowering of cAMP is required for downregulation of SERCA2 mRNA levels. Increasing intracellular cAMP quantity using cAMP-specific PDE inhibitor Ro20-1724 or cAMP analog dibutyryl-cAMP reverses ET-induced downregulation of SERCA2 mRNA levels. The data indicate that, in adult myocytes, ET downregulates SERCA2 mRNA and protein levels, and the effect requires cross-talk between Gq and PTX-sensitive Gi pathways.

hypertrophy; sarcoplasmic reticulum calcium ATPase; Gi; Gq


Address for reprint requests and other correspondence: R. Hilal-Dandan, Univ. of California, San Diego, Dept. of Pharmacology, 9500 Gilman Dr., La Jolla, CA 92093-0636 (e-mail: rdandan{at}ucsd.edu)




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 Circ Heart FailHome page
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On the Control of Metabolic Remodeling in Mitochondria of the Failing Heart
Circ Heart Fail, July 1, 2009; 2(4): 275 - 277.
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