1,25-dihydroxyvitamin d3 regulation of cardiac myocyte
proliferation and hypertrophy.
Ooconnell, Timothy D., Janice E. Berry, Amy K. Jarvis, Martha J.
Somerman, and Robert U. Simpson.
The Department of Pharmacology, The University of Michigan, 1301
MSRB III, 1150 W. Medical Center Dr., Ann Arbor MI, 48109-0632, (313)
763-3325, Fax: (313) 763-4450, The Department of
Periodontics/Prevention/Geriatrics, School of Dentistry, The
University of Michigan, 1101 N. University, Ann Arbor MI, 48109-0632,
(313) 763-3388, Fax: (313) 764-1562
APStracts 3:0541H, 1996.
We previously demonstrated that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)
inhibits myocyte maturation (OOConnell et al. 1995 Endocrinology 136:
482-488). To define further the role of 1,25(OH)2D3 in regulating
myocardial development, we examined the effects of 1,25(OH)2D3 on
proliferation and growth of primary cultures of ventricular myocytes
isolated from neonatal rat hearts. When neonatal myocytes were grown
in a serum-supplemented medium, cell number approximately doubled,
and treating these myocytes with 1,25(OH)2D3 inhibited their
proliferation by 56.56% after four days. Flow cytometry revealed that
1,25(OH)2D3 reduced the percent of cells in the S-phase of the cell
cycle by 31.39% after four days. In this report we show for the first
time that proliferating cell nuclear antigen (PCNA) protein levels
were specifically reduced by 1,25(OH)2D3. Proto-oncogene c-myc
protein levels were also reduced by this hormone. Interestingly, a
phorbol ester had a similar effect on myocyte proliferation.
Furthermore, 1,25(OH)2D3 increased myocyte protein levels and
increased cell size, suggesting that it induces cardiac myocyte
hypertrophy. Our findings indicate that both 1,25(OH)2D3 and phorbol
esters directly regulate myocyte proliferation and induce myocyte
hypertrophy. Finally, the data demonstrate that the mechanism by
which 1,25(OH)2D3 regulates myocyte proliferation involves blocking
entry into the S-phase of the cell cycle.
Received 30 April 1996; accepted in final form 6 November 1996.
APS Manuscript Number H386-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996