ABSTRACT
Cardiolipin, a unique phospholipid in the inner mitochondrial membrane, is critical for optimal mitochondrial function. CL abnormalities have been demonstrated in the failing rodent and adult human heart. The aim of this study was to determine whether abnormalities in CL content and the CL biosynthesis and remodeling pathways are present in pediatric idiopathic dilated cardiomyopathy (IDC). A cross-sectional analysis of myocardial tissue from 119 IDC and non-failing (NF) control samples was performed. Electrospray ionizing mass spectrometry was used to measure total CL and CL species content in LV tissue. RT-PCR was employed to measure gene expression of the enzymes in the CL biosynthesis and remodeling pathways in both the adult and pediatric heart. Significantly lower total and (18:2)4CL (the beneficial species) content was demonstrated in myocardium from pediatric patients with IDC compared to NF controls. Analysis of mitochondrial gene transcripts was used to demonstrate that there is no decrease in mitochondrial content. Expression of two biosynthesis enzymes and one remodeling enzyme was significantly lower in pediatric IDC compared to NF controls. Expression of two phospholipases involved in CL degradation were also altered, one up- and one down-regulated. Except for one remodeling enzyme, these changes are unique from those in the failing adult heart. Similar to what has been seen in adults and in a rat model of IDC, total and (18:2)4CL are lower in pediatric IDC. Unique CL species profiles are seen in heart tissue from children with IDC compared to adults. Differences in CL biosynthesis and remodeling enzyme expression likely explain the differences in CL profiles observed in IDC and implicate unique age-related mechanisms of disease.
Subject(s)
Cardiolipins/biosynthesis , Cardiomyopathy, Dilated/metabolism , Heart Failure/metabolism , Heart Ventricles/metabolism , Mitochondria, Heart/metabolism , Myocardium/metabolism , Adolescent , Adult , Age Factors , Aged , Cardiolipins/chemistry , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Dilated/surgery , Child , Child, Preschool , Female , Gene Expression , Heart Failure/pathology , Heart Failure/surgery , Heart Transplantation , Heart Ventricles/pathology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Mitochondria, Heart/pathology , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Myocardium/pathologyABSTRACT
Children with heart failure are treated with similar medical therapy as adults with heart failure. In contrast to adults with heart failure, these treatment regiments are not associated with improved outcomes in children. Recent studies have demonstrated age-related pathophysiological differences in the molecular mechanisms of heart failure between children and adults. There are no animal models of pediatric cardiomyopathy to allow mechanistic studies. The purpose of the current experiments was to develop a mouse model of pediatric heart disease and test whether the influence of ß-adrenergic receptor (ß-AR) antagonism could be modeled in this system. We hypothesized that isoproterenol treatment of young mice would provide a model system of cardiac pathology, and that nonselective ß-AR blockade would provide benefit in adult, but not young, mice, similar to clinical trial data. We found that isoproterenol treatment (through osmotic minipump implantation) of young and adult mice produced similar degrees of cardiac hypertrophy and recapitulated several age-related molecular abnormalities in human heart failure, including phospholamban phosphorylation and ß-AR expression. We also found that nonselective ß-AR blockade effectively prevented pathological cardiac growth and collagen expression in the adult but not young mice, and that selective ß1-AR blockade was effective in both young and adult isoproterenol-treated mice. In conclusion, we have developed the first model system for ß-AR-mediated pediatric heart disease. Furthermore, we have generated novel data suggesting beneficial effects of selective ß1-AR blockade in the pediatric heart.
Subject(s)
Adrenergic beta-1 Receptor Antagonists/pharmacology , Heart Diseases/drug therapy , Heart Diseases/metabolism , Receptors, Adrenergic, beta/metabolism , Animals , Child , Disease Models, Animal , Heart/drug effects , Humans , Isoproterenol/pharmacology , MiceABSTRACT
Decreases in cardiac connexin43 (Cx43) play a critical role in abnormal cell-to-cell communication and have been linked to the resistance of the female heart to arrhythmias. We therefore hypothesized that Cx43 expression would be greater in female cardiomyocytes than in male cardiomyocytes under pathologic conditions. Adult ventricular myocytes were isolated from male and female rats and treated with phenylephrine (PE), a well-established pathologic stimulus. Cx43 gene and protein expression was determined. The expression of micro-RNA-1 (miR-1), a micro-RNA known to control Cx43 protein expression in cardiomyocytes, was also determined. Cx43 mRNA and protein levels were significantly higher in the female cardiomyocytes than in the male cardiomyocytes (mRNA: 1.4-fold; Protein: 5-fold, both P < 0.05) under both basal and pathologic conditions. PE treatment increased Cx43 expression only in female cardiomyocytes. Cx43 phosphorylation, a marker of preserved Cx43 function, was also higher (P < 0.05), and The expression of miR-1 was lower (P < 0.05) in the female cardiomyocytes after PE treatment. The expression of miR-1 was unchanged by PE treatment in male cardiomyocytes. Thus, a sex difference in miR-1 may be responsible for the sex difference in Cx43 expression in cardiomyocytes under pathologic conditions. Taken together, our results demonstrate a sex difference in Cx43 expression and site-specific phosphorylation that favors cardioprotection in female cardiomyocytes.
