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A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response.

Publication ,  Journal Article
Seldin, MM; Kim, ED; Romay, MC; Li, S; Rau, CD; Wang, JJ; Krishnan, KC; Wang, Y; Deb, A; Lusis, AJ
Published in: Am J Physiol Heart Circ Physiol
April 1, 2017

Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.

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Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

April 1, 2017

Volume

312

Issue

4

Start / End Page

H728 / H741

Location

United States

Related Subject Headings

  • Transcription Factors
  • Substrate Specificity
  • Rats
  • RNA, Small Interfering
  • Myocytes, Cardiac
  • Mice
  • Isoproterenol
  • In Vitro Techniques
  • Glycolysis
  • Glycogen
 

Citation

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Seldin, M. M., Kim, E. D., Romay, M. C., Li, S., Rau, C. D., Wang, J. J., … Lusis, A. J. (2017). A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response. Am J Physiol Heart Circ Physiol, 312(4), H728–H741. https://doi.org/10.1152/ajpheart.00068.2016
Seldin, Marcus M., Eric D. Kim, Milagros C. Romay, Shen Li, Christoph D. Rau, Jessica J. Wang, Karthickeyan Chella Krishnan, Yibin Wang, Arjun Deb, and Aldons J. Lusis. “A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response.Am J Physiol Heart Circ Physiol 312, no. 4 (April 1, 2017): H728–41. https://doi.org/10.1152/ajpheart.00068.2016.
Seldin MM, Kim ED, Romay MC, Li S, Rau CD, Wang JJ, et al. A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response. Am J Physiol Heart Circ Physiol. 2017 Apr 1;312(4):H728–41.
Seldin, Marcus M., et al. “A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response.Am J Physiol Heart Circ Physiol, vol. 312, no. 4, Apr. 2017, pp. H728–41. Pubmed, doi:10.1152/ajpheart.00068.2016.
Seldin MM, Kim ED, Romay MC, Li S, Rau CD, Wang JJ, Krishnan KC, Wang Y, Deb A, Lusis AJ. A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response. Am J Physiol Heart Circ Physiol. 2017 Apr 1;312(4):H728–H741.

Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

April 1, 2017

Volume

312

Issue

4

Start / End Page

H728 / H741

Location

United States

Related Subject Headings

  • Transcription Factors
  • Substrate Specificity
  • Rats
  • RNA, Small Interfering
  • Myocytes, Cardiac
  • Mice
  • Isoproterenol
  • In Vitro Techniques
  • Glycolysis
  • Glycogen