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Conditionally targeted deletion of PSEN1 leads to diastolic heart dysfunction
- Source :
- Journal of Cellular Physiology. 233:1548-1557
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 10974652 and 00219541
- Volume :
- 233
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular Physiology
- Accession number :
- edsair.doi.dedup.....4a65f013d43c4be0336371bdce42b376