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Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity.

ABSTRACT: The identification and characterization of the cellular and molecular pathways involved in the differentiation and morphogenesis of specific cell types of the developing heart are crucial to understanding the process of cardiac development and the pathology associated with human congenital heart disease. Here, we show that the cardiac transcription factor CASTOR (CASZ1) directly interacts with congenital heart disease 5 protein (CHD5), which is also known as tryptophan-rich basic protein (WRB), a gene located on chromosome 21 in the proposed region responsible for congenital heart disease in individuals with Down's syndrome. We demonstrate that loss of CHD5 in Xenopus leads to compromised myocardial integrity, improper deposition of basement membrane, and a resultant failure of hearts to undergo cell movements associated with cardiac formation. We further report that CHD5 is essential for CASZ1 function and that the CHD5-CASZ1 interaction is necessary for cardiac morphogenesis. Collectively, these results establish a role for CHD5 and CASZ1 in the early stages of vertebrate cardiac development.

SUBMITTER: Sojka S

PROVIDER: S-EPMC4197678 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity.

Sojka Stephen S Amin Nirav M NM Gibbs Devin D Christine Kathleen S KS Charpentier Marta S MS Conlon Frank L FL

Development (Cambridge, England) 20140703 15

The identification and characterization of the cellular and molecular pathways involved in the differentiation and morphogenesis of specific cell types of the developing heart are crucial to understanding the process of cardiac development and the pathology associated with human congenital heart disease. Here, we show that the cardiac transcription factor CASTOR (CASZ1) directly interacts with congenital heart disease 5 protein (CHD5), which is also known as tryptophan-rich basic protein (WRB), ...[more]

PMID: 24993940

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Project description:BackgroundIn patients with complex congenital heart disease, such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload stress, leading to RV hypertrophy and eventually RV failure. The role of lipid peroxidation, a potent form of oxidative stress, in mediating RV hypertrophy and failure in congenital heart disease is unknown.MethodsLipid peroxidation and mitochondrial function and structure were assessed in right ventricle (RV) myocardium collected from patients with RV hypertrophy with normal RV systolic function (RV fractional area change, 47.3±3.8%) and in patients with RV failure showing decreased RV systolic function (RV fractional area change, 26.6±3.1%). The mechanism of the effect of lipid peroxidation, mediated by 4-hydroxynonenal ([4HNE] a byproduct of lipid peroxidation) on mitochondrial function and structure was assessed in HL1 murine cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes.ResultsRV failure was characterized by an increase in 4HNE adduction of metabolic and mitochondrial proteins (16 of 27 identified proteins), in particular electron transport chain proteins. Sarcomeric (myosin) and cytoskeletal proteins (desmin, tubulin) also underwent 4HNE adduction. RV failure showed lower oxidative phosphorylation (moderate RV hypertrophy, 287.6±19.75 versus RV failure, 137.8±11.57 pmol/[sec×mL]; P=0.0004), and mitochondrial structural damage. Using a cell model, we show that 4HNE decreases cell number and oxidative phosphorylation (control, 388.1±23.54 versus 4HNE, 143.7±11.64 pmol/[sec×mL]; P<0.0001). Carvedilol, a known antioxidant did not decrease 4HNE adduction of metabolic and mitochondrial proteins and did not improve oxidative phosphorylation.ConclusionsMetabolic, mitochondrial, sarcomeric, and cytoskeletal proteins are susceptible to 4HNE-adduction in patients with RV failure. 4HNE decreases mitochondrial oxygen consumption by inhibiting electron transport chain complexes. Carvedilol did not improve the 4HNE-mediated decrease in oxygen consumption. Strategies to decrease lipid peroxidation could improve mitochondrial energy generation and cardiomyocyte survival and improve RV failure in patients with congenital heart disease.

Project description:BackgroundThe population of adults with congenital heart disease (CHD) is growing, and increasingly more patients with CHD reach older ages. Patients with CHD are at an increased risk of myocardial infarction (MI) with increased age. Diagnosing MI in patients with CHD can be challenging in clinical practice owing to a high prevalence of aberrant electrocardiograms, ventricular hypertrophy, and heart failure, among other factors. The National Swedish Patient Register (NPR) is widely used in epidemiological studies; however, MI diagnoses specifically in patients with CHD have never been validated in the NPR.MethodsWe contacted hospitals and medical archive services to request medical records for 249 patients, born during 1970-2012, with both CHD and MI diagnoses and who were randomly selected from the NPR by the Swedish National Board of Health and Welfare. Follow-up was until 2015. We performed a medical chart review to validate the MI diagnoses; we also validated CHD diagnoses to ensure that only patients with confirmed CHD diagnoses were included in the MI validation process.ResultsWe received medical records for 96.4% (n = 238/249) of patients for validation of CHD diagnoses. In total, 74.8% (n = 178/238) had a confirmed CHD diagnosis; of these, 70.2% (n = 167) had a fully correct CHD diagnosis in the NPR; a further 4.6% (n = 11) had a CHD diagnosis, but it was misclassified. MI diagnoses were validated in 167 (93.8%) patients with confirmed CHD. Of the patients with confirmed CHD, 88.0% (n = 147/167) had correct MI diagnoses. Patients with non-complex CHD diagnoses had more correct MI diagnoses than patients with complex CHD (91.0%, n = 131 compared with 69.6%, n = 16). The main cause for incorrect MI diagnoses was typographical error, contributing to 50.0% of the incorrect diagnoses.ConclusionsThe validity of MI diagnoses in patients with confirmed CHD in the NPR is high, with nearly 9 of 10 MI diagnoses being correct (88.0%). MI in patients with CHD can safely be studied using the NPR.

Dataset Information

Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity.

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Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity.

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