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 Field

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 β-adrenergic stimulation can reactivate the cell cycle in a limited number of terminally differentiated adult cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)1069-1077
Number of pages9
JournalCirculation Research
Volume86
Issue number10
StatePublished - May 26 2000

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Transgenes
Cardiac Myocytes
Hypertrophy
Complementary DNA
DNA
Genes
NIH 3T3 Cells
Inborn Genetic Diseases
Tuberous Sclerosis
Protein Transport
Growth
Endocytosis
Isoproterenol
Adrenergic Agents
Transgenic Mice
Disease Progression
Neoplasms
Cell Cycle
Phenotype
Gene Expression

Keywords

  • Cardiac regeneration
  • Tumor suppressor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene. / Pasumarthi, Kishore B S; Nakajima, Hidehiro; Nakajima, Hisako O.; Jing, Shaoliang; Field, Loren.

In: Circulation Research, Vol. 86, No. 10, 26.05.2000, p. 1069-1077.

Research output: Contribution to journalArticle

Pasumarthi, KBS, Nakajima, H, Nakajima, HO, Jing, S & Field, L 2000, 'Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene', Circulation Research, vol. 86, no. 10, pp. 1069-1077.
Pasumarthi, Kishore B S ; Nakajima, Hidehiro ; Nakajima, Hisako O. ; Jing, Shaoliang ; Field, Loren. / Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene. In: Circulation Research. 2000 ; Vol. 86, No. 10. pp. 1069-1077.
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