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Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency
Christina V. Theodoris, … , Helen M. Blau, Deepak Srivastava
Christina V. Theodoris, … , Helen M. Blau, Deepak Srivastava
Published March 27, 2017
Citation Information: J Clin Invest. 2017;127(5):1683-1688. https://doi.org/10.1172/JCI90338.
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Brief Report Cardiology

Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency

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Abstract

Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency. Furthermore, progressive telomere shortening correlated with severity of disease, causing cardiac valve and septal disease in the neonate that was similar to the range of valve disease observed within human families. Genes that were dysregulated due to NOTCH1 haploinsufficiency in mice with shortened telomeres were concordant with proosteoblast and proinflammatory gene network alterations in human NOTCH1 heterozygous endothelial cells. These dysregulated genes were enriched for telomere-contacting promoters, suggesting a potential mechanism for telomere-dependent regulation of homeostatic gene expression. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease and provide an in vivo model in which to test therapeutic candidates targeting the progression of aortic valve disease.

Authors

Christina V. Theodoris, Foteini Mourkioti, Yu Huang, Sanjeev S. Ranade, Lei Liu, Helen M. Blau, Deepak Srivastava

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Figure 1

Telomere shortening elicits age-dependent AV calcification in N1+/– mice.

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Telomere shortening elicits age-dependent AV calcification in N1+/– mice...
(A) AV peak velocity by echocardiography (N1WT mTRG2, n = 15; N1+/− mTRG2, n = 26). Boxes show interquartile range (IQR); whiskers indicate range; lines indicate median. Red, female; blue, male. *P < 0.05, 1-sided t test. (B) Mean AV leaflet maximum thickness (N1WT mTRG2, n = 14; N1+/− mTRG2, n = 22). Data are shown as mean ± SEM. *P < 0.05, 1-sided t test.(C) Alizarin staining (red) of calcification in AVs (N1WT mTRG2, 0% Alizarin positive, n = 16; N1+/− mTRG2 with normal echocardiograms, 30% Alizarin positive, n = 17; N1+/− mTRG2 with AS by echocardiography, 100% Alizarin positive, n = 4). *P < 0.05, χ2 test. Boxes in upper row indicate region magnified in corresponding images in lower row. (D) Alizarin staining of calcification in aorta. Arrowheads indicate aortic wall. (E) RUNX2 and DAPI immunohistochemistry of AVs. N1+/− mTRG2 RUNX2-stained section is adjacent to bottom right Alizarin-stained section in C.
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