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(Circulation Research. 2000;86:1069.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Enhanced Cardiomyocyte DNA Synthesis During Myocardial Hypertrophy in Mice Expressing a Modified TSC2 Transgene

Kishore B. S. Pasumarthi, Hidehiro Nakajima, Hisako O. Nakajima, Shaoliang Jing, Loren J. Field

From the Wells Center for Pediatric Research and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Ind.

Correspondence to Loren J. Field, Herman B Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, 702 Barnhill Dr, Room 2600, Indianapolis, IN 46202-5225. E-mail ljfield{at}iupui.edu

Abstract—Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the appearance of benign tumors in multiple organs, including the heart. Disease progression is accompanied by homozygous mutation at 1 of 2 loci (designated TSC1 or TSC2), leading to the suggestion that these genes function as tumor suppressors. In this study, we generated a series of TSC2 cDNAs in which one or more structural motifs were deleted, with the hope that expression of the modified gene product would override the growth-inhibitory activity of the endogenous TSC2 gene product. Several of the modified cDNAs enhanced growth rate, increased endocytosis, and promoted aberrant protein trafficking when expressed in NIH-3T3 cells, thereby mimicking phenotypes typical of TSC2-deficient cells. Surprisingly, targeted expression of the most potent TSC2 cDNA to the heart did not perturb cardiac development. However, the level of cardiomyocyte DNA synthesis in adult transgenic mice was elevated >35-fold during isoproterenol-induced hypertrophy compared with their nontransgenic siblings. These results suggest that alteration of TSC2 gene activity in combination with ß-adrenergic stimulation can reactivate the cell cycle in a limited number of terminally differentiated adult cardiomyocytes.

Key Words: tumor suppressor • cardiac regeneration

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