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.
Subject(s)
Gene Deletion , Heart Defects, Congenital/physiopathology , Presenilin-1/deficiency , Ventricular Dysfunction, Left/physiopathology , Ventricular Function, Left , Animals , Diastole , Gene Expression Regulation , Genetic Predisposition to Disease , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Mice, Knockout , Myocardial Ischemia/genetics , Myocardial Ischemia/metabolism , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/ultrastructure , Phenotype , Presenilin-1/genetics , Ventricular Dysfunction, Left/genetics , Ventricular Dysfunction, Left/metabolism , Ventricular Dysfunction, Left/pathologyABSTRACT
intracellular Ca(2+) handling by the sarcoplasmic reticulum (SR) plays a crucial role in the pathogenesis of heart failure (HF). Despite extensive effort, the underlying causes of abnormal SR Ca(2+) handling in HF have not been clarified. To determine whether the diastolic SR Ca(2+) leak along with reduced Ca(2+) reuptake is required for decreased contractility, we investigated the cytosolic Ca(2+) transients and SR Ca(2+) content and assessed the expression of ryanodine receptor (RyR2), FK506 binding protein (FKBP12.6), SR-Ca(2+) ATPase (SERCA2a), and L-type Ca(2+) channel (LTCC) using an SD-rat model of chronic HF. We found that the cytosolic Ca(2+) transients were markedly reduced in amplitude in HF myocytes (DeltaF/F(0) = 12.3 +/- 0.8) compared with control myocytes (DeltaF/F(0) = 17.7 +/- 1.2, P < 0.01), changes paralleled by a significant reduction in the SR Ca(2+) content (HF: DeltaF/F(0) = 12.4 +/- 1.1, control: DeltaF/F(0) = 32.4 +/- 1.9, P < 0.01). Moreover, we demonstrated that the expression of FKBP12.6 associated with RyR2, SERCA2a, and LTCC was significantly reduced in rat HF. These results provide evidence for phosphorylation-induced detachment of FKBP12.6 from RyRs and down-regulation of SERCA2a and LTCC in HF. We conclude that diastolic SR Ca(2+) leak (due to dissociation of FKBP12.6 from RyR2) along with reduced SR Ca(2+) uptake (due to down-regulation of SERCA2a) and defective E-C coupling (due to down-regulation of LTCC) could contribute to HF.
