Dual Expression and Differential Regulation of Phosphodiesterase 3A and Phosphodiesterase 3B in Human Vascular Smooth Muscle: Implications for Phosphodiesterase 3 Inhibition in Human Cardiovascular Tissues
- 1Department of Pharmacology & Toxicology (D.P., D.H.M.) and2Department of Pathology (D.H.M.), Queen's University, Kingston, Ontario, Canada
Abstract
Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes whose physiological role is the attenuation of the signaling mediated by the ubiquitous second messengers cAMP and cGMP. Given the myriad of physiological processes regulated by cAMP and cGMP, PDEs have long been studied as potential therapeutic targets. Although phosphodiesterase 3 (PDE3) activity is abundant in human cardiovascular tissues, and acute PDE3 inhibition, with agents such as milrinone, was beneficial in heart failure patients, prolonged treatments were associated with time-dependent reductions in hemodynamic effects and increased mortality. The molecular basis of this time-dependent reduction in efficacy has not been elucidated. In this context, we used a combination of approaches to determine PDE3 expression in human cardiovascular tissues and to elucidate the effects of prolonged elevations of cellular cAMP, as would occur with PDE3 inhibition, on this activity. Although our data confirms the expression of PDE3A in human blood vessel smooth muscle cells (HASMCs), we identify a previously unrecognized role for PDE3B in cAMP hydrolysis in human cardiovascular tissues. Specifically, although both PDE3A and PDE3B were expressed in HASMCs, their subcellular expression pattern and regulated expression by cAMP were distinct, with only expression of PDE3B being subject to cAMP-regulated expression. Thus, a paradigm emerges that allows for dual expression, with distinctive regulation, of both PDE3A and PDE3B proteins in cardiovascular tissues that may have profound significance for the rational design of molecules regulating this PDE activity.
Footnotes
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Send reprint requests to: Dr. Donald H. Maurice, A221 Botterell Hall, Department of Pharmacology & Toxicology, Queen's University, Kingston, ON, Canada, K7L 3N6. E-mail:Mauriced{at}post.queensu.ca
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Support for this study came from the Heart and Stroke Foundation of Ontario (Grant-in-aid T-3671) and the Medical Research Council of Canada (Grant-in-aid MT-15540). D.P. was the recipient of an Ontario Graduate Scholarship and a Medical Research Council of Canada Doctoral Research Award. D.H.M. is a Career Research Scientist in Health Sciences sponsored by the Pharmaceutical Manufacturer's Association of Canada-Health Research Foundation/Medical Research Council of Canada.
- Abbreviations:
- Abbreviations
- PDEs, cyclic nucleotide phosphodiesterases
- PDE3
- phosphodiesterase 3
- HASMCs
- human aortic smooth muscle cells
- RASMCs
- rat aortic smooth muscle cells
- N6,O2′-dibutyryl cAMP
- DbcAMP
- CHF
- congestive heart failure
- bp
- base pair(s)
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- Received February 23, 2000.
- Accepted May 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
