Preserved heart function after left ventricular pressure overload in adult mice subjected to neonatal cardiac hypoplasia.

Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such incomplete cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. We have previously described a mouse model of impaired myocardial development leading to a 25% reduction of cardiomyocyte number in neonates. This study investigated the response of these hypoplastic hearts to pressure overload in adulthood, applied by abdominal aortic constriction (AAC). Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks. Subsequently, control mice develop mild left ventricular (LV) dilation, wall thinning and contractile dysfunction 4 weeks after AAC, whereas hypoplastic hearts fully maintain LV dimensions, wall thickness and contractility. At the cellular level, controls exhibit increased cardiomyocyte cross-sectional area after 4 weeks pressure overload compared with sham operated animals, but this hypertrophic response is markedly attenuated in hypoplastic hearts. AAC mediated induction of fibrosis, apoptosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, pressure overload induces p38 MAP-kinase activity in hypoplastic hearts but not controls compared with the respective sham operated animals. In summary, based on the mouse model used in this study, our data indicates that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls.

Identification of the human ortholog of the t-complex-encoded protein TCTE3 and evaluation as a candidate gene for primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive disease that is caused by impaired ciliary and flagellar functions. About 50% of PCD patients show situs inversus, denoted as Kartagener syndrome. In most cases, axonemal defects in cilia and sperm tails can be demonstrated by electron microscopy, i.e. PCD patients often lack inner and/or outer dynein arms in their sperm tails and cilia, supporting the hypothesis that mutations in dynein genes may cause PCD. In order to identify novel PCD genes we have isolated the human ortholog of the murine TCTE3 gene. The human TCTE3 gene encodes a dynein light chain and shares high similarity to dynein light chains of other species. The TCTE3 gene is expressed in tissues containing cilia or flagella, it is composed of four exons and located on chromosome 6q25-->q27. To elucidate the role of TCTE3 as a candidate gene for PCD a mutational analysis of thirty-six PCD patients was performed. We detected five polymorphisms in the coding sequence and in the 5' UTR of the TCTE3 gene. In one patient a heterozygous nucleotide exchange was identified resulting in an arginine to isoleucine substitution at the amino acid level. However, this exchange was also detected in one control DNA. Our results indicate that mutations in the TCTE3 gene are not a main cause of primary ciliary dyskinesia.