ABSTRACT
Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia-induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a-PSEN1-KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a-PSEN1-KO group compared with the percent of these measures in the WT group, indicating that PSEN1-KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1-KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca2+ ion channels, promoting us to investigate the effects of PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in isolated adult cardiomyocytes, PSEN1-KO increased the concentration of cytosolic Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout mice. These results indicate that the process of Ca2+ release from SR into cytoplasm was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis resulted from downregulation of PSEN1 in failing hearts might contribute to aging-related cardiomyopathy, which might had important implications for the treatment of aging-related heart diseases.
Subject(s)
Calcium , Cardiomyopathy, Dilated , Animals , Cardiomyopathy, Dilated/genetics , Homeostasis , Mice , Mice, Knockout , Myocytes, Cardiac/physiology , Sarcoplasmic ReticulumABSTRACT
For normal-weight population, the management of prehypertension may be more beneficial by identifying insulin resistance (IR) status than relying solely on traditional indicators of obesity. We investigated the association of triglyceride glucose (TyG) index, a simple surrogate marker of IR, and its combination of obesity indices with prehypertension in lean individuals. A total of 105 070 lean adults without hypertension were included in this analysis. Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WtHR), and TyG were calculated according to the corresponding formula; TyG-BMI, TyG-WC, and TyG-WHtR were calculated by multiplying the corresponding two parameters. Gardner-Altman plots, partial correlation, and logistic regression analyses were applied to explore the associations in continuous variables and quartiles. The prehypertensive ones had higher mean values of TyG, TyG-BMI, TyG-WC, and TyG-WHtR than normotensive individuals. All the four indicators showed positive correlations with systolic blood pressure and diastolic blood pressure. After full adjustment, only TyG-BMI and TyG-WC were significantly associated with prehypertension in both genders. Furthermore, TyG-BMI had the highest OR for prehypertension. Our study showed that TyG-BMI might be an accessible and complementary monitor in the hierarchical management of non-obese prehypertensive patients.
Subject(s)
Glucose , Hypertension , Prehypertension , Triglycerides , Adult , Blood Glucose/metabolism , Body Mass Index , China/epidemiology , Cross-Sectional Studies , Female , Glucose/metabolism , Humans , Hypertension/diagnosis , Hypertension/epidemiology , Hypertension/metabolism , Male , Obesity/diagnosis , Obesity/epidemiology , Obesity/metabolism , Prehypertension/diagnosis , Prehypertension/epidemiology , Prehypertension/metabolism , Risk Factors , Triglycerides/metabolismABSTRACT
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
Autophagy is an adaptive response to cardiomyocytes survival under stress conditions. MicroRNAs (miRNAs, miR) have been described to act as potent modulators of autophagy. To investigate whether and how miR-199a modulated autophagy in vitro, primary cardiomyocytes were treated under starvation to induce autophagy. Results showed that down-regulation of miR-199a was sufficient to activate cardiomyocytes autophagy. MiR-199a suppressed cardiomyocytes autophagy through direct inhibiting heat shock protein family A member 5 (Hspa5). Forced overexpression of Hspa5 recovered the inhibitory effect of miR-199a in autophagy activation. Our results suggested miR-199a as an effective suppressor of starvation-induced cardiomyocytes autophagy and that Hspa5 was a direct target during this process. These results extend the understanding of the role and pathway of miR-199a in cardiomyocytes autophagy, and may introduce a potential therapeutic strategy for the protection of cardiomyocytes in myocardial infarction or ischemic heart disease.
