Hesr2 knockout mice develop aortic valve disease with advancing age

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Developmental Biology

Background:

• Acquired heart diseases, including valve disease, significantly contribute to human morbidity and mortality.
• The underlying pathological mechanisms of many acquired heart diseases remain largely unknown.
• The role of specific genes, like Hesr2, in adult heart physiology requires further elucidation.

Purpose of the Study:

• To investigate the function of the hairy and enhancer of split-related (Hesr)-2 gene in the adult mammalian heart.
• To identify the specific contribution of Hesr2 to the development and progression of aortic valve disease.
• To understand the impact of Hesr2 deficiency on cardiac structure and function.

Main Methods:

• Generation and analysis of Hesr2 knockout mice.
• Echocardiography to assess cardiac function and valve morphology.
• Morphological and histological analyses of cardiac tissues.
• Gene expression analysis of osteogenic markers.

Main Results:

• Hesr2 knockout mice exhibited significant aortic valve anomalies, including stenosis and regurgitation, in approximately 59% of survivors.
• Histological analysis revealed thickened, fibrotic semilunar valves, indicative of sclerotic degeneration.
• Upregulation of osteogenic genes (osteopontin, sclerostin) was observed in Hesr2 mutants, with sclerostin overexpression mimicking valve pathology.
• Reduced left ventricular function and interstitial fibrosis were noted, with dilated ventricles in mice with aortic valve disease, suggesting hemodynamic influence.

Conclusions:

• Loss of Hesr2 in adult mice leads to aortic valve fibrosis and ventricular dysfunction.
• Hesr2 plays a critical role in maintaining the structural and functional integrity of the aortic valve and ventricle.
• Hesr2 may regulate osteogenic gene expression within the valves, contributing to valve homeostasis.