Hesr2 knockout mice develop aortic valve disease with advancing age

Hiroki Kokubo*, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Tsutomu Kume, Masao Yoshizumi, Toshio Nakanishi, Yumiko Saga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Objective-Acquired heart diseases, such as valve disease, are major causes of human morbidity and mortality. However, the pathological mechanisms underlying these diseases are largely unknown. Our aim is to identify the role of the hairy and enhancer of split-related (Hesr)-2 gene in the adult heart. Methods and Results-Echocardiography detected heart dysfunctions indicative of aortic valve anomalies, stenosis, and regurgitation, in ≈59% of >12-month-old Hesr2 knockout survivor mice. Morphological and histological analyses revealed thickened semilunar valves with increased fibrotic areas, indicating that sclerotic degeneration of valves is the main cause of aortic valve disease. The expression of osteogenic genes, such as Osteopontin and Sclerostin, were upregulated in the mutants, and the overexpression of Sclerostin in endothelial cells resulted in thickened semilunar valves with increased fibrotic areas, similar to that seen in the Hesr2 knockout mice, suggesting that Hesr2 can regulate osteogenic gene expression in valves. Reduced left ventricular function, which may be caused by increased ventricular interstitial fibrosis, and enlarged myocardial cell size without ventricular wall thickening were found in both aortic valve stenosis/regurgitation-positive (33%) and aortic valve stenosis/regurgitation-negative (38%) subpopulations in 12-month-old survivor mice. Dilated left ventricular internal dimensions were specifically detected in the aortic valve stenosis/regurgitation-positive subpopulation, thus suggesting that the degeneration of cardiomyocytes is influenced by irregular hemodynamics. Conclusion-These data revealed that survivor mice lacking the Hesr2 gene exhibit fibrosis in the aortic valve and ventricle in adulthood, thus suggesting that Hesr2 plays an important role in maintaining the homeostasis of the aortic valve and ventricle.

Original languageEnglish (US)
Pages (from-to)e84-e92
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number3
StatePublished - Mar 2013


  • Hesr2/Hey2
  • aging
  • fibrosis
  • valve disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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