Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction
| Autor: | Tang Ying, Changhai Lei, Yong-Ji Yang, Ya-feng Shen, XiaoWei Song, Xianxian Zhao, Zhen-Yu Zeng, Mi Cao, Qingning Yuan, Song-hua Li |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Heart Defects
Congenital 0301 basic medicine medicine.medical_specialty Physiology Heart growth Clinical Biochemistry Myocardial Ischemia Cardiomyopathy Diastole Biology Ventricular Function Left Muscle hypertrophy Ventricular Dysfunction Left 03 medical and health sciences 0302 clinical medicine Internal medicine Presenilin-1 medicine Animals Genetic Predisposition to Disease Myocytes Cardiac Mice Knockout Dilated cardiomyopathy Cell Biology medicine.disease Phenotype 030104 developmental biology Endocrinology medicine.anatomical_structure Gene Expression Regulation Ventricle Heart failure Knockout mouse Hypertrophy Left Ventricular Gene Deletion 030217 neurology & neurosurgery |
| Zdroj: | Journal of Cellular Physiology. 233:1548-1557 |
| ISSN: | 1097-4652 0021-9541 |
| DOI: | 10.1002/jcp.26057 |
| Popis: | Recently, PSEN1 has been reported to have mutations in dilated cardiomyopathy pedigrees. However, the function and mechanism of PSEN1 in cardiomyopathy remains unresolved. Here, we established four types of genetically modified mice to determine the function of PSEN1 in cardiac development and pathology. PSEN1 null mutation resulted in perinatal death, retardation of heart growth, ventricular dilatation, septum defects, and valvular thickening. PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and reduced lengths of sarcomeres in cardiomyocytes. Cardiovascular loss of function of PSEN1 induced by Sm22a-Cre or Myh6-Cre/ER/tamoxifen also resulted in severe ultrastructural abnormalities, such as relaxed gap junctions between neighboring cardiomyocytes. Functionally, cardiovascular deletion of PSEN1 caused spontaneous mortality from birth to adulthood and led to diastolic heart dysfunction, including decreased volume of the left ventricle at the end-systolic and end-diastolic stages. Additionally, in a myocardial ischemia model, deletion of PSEN1 in the cardiovascular system first protected mice by inducing adaptive hypertrophy but ultimately resulted in severe heart failure. Furthermore, a collection of genes was abnormally expressed in the hearts of cardiac-specific PSEN1 knockout mice. They were enriched in cell proliferation, calcium regulation, and so on. Taken together, dynamic regulation and abnormal function of PSEN1 underlie the pathogenesis of cardiovascular diseases due to ultrastructural abnormality of cardiomyocytes. |
| Databáze: | OpenAIRE |
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