👤 Theodor K Bammler

Pre-pregnancy obesity (ppOB) is linked to pregnancy complications and abnormal fetal growth through placental mechanisms, and long non-coding RNAs (lncRNAs) may play an epigenetic role in these processes. We investigated overall and sex-specific associations of pre-pregnancy body mass index (ppBMI), ppOB, and birthweight with placental lncRNA transcripts in two birth cohorts. Study participants were mother-child dyads recruited to the CANDLE (Memphis, TN)( Show less

We have previously found that overexpression of CHF1/Hey2 in the myocardium prevents the development of phenylephrine-induced hypertrophy. To identify transcriptional pathways regulated by CHF1/Hey2, we cultured primary neonatal mouse cardiac myocytes from wild type and transgenic mice overexpressing CHF1/Hey2 and treated them with serum, a potent hypertrophic stimulus. We verified that overexpression of CHF1/Hey2 suppressed cardiac myocyte hypertrophy induced by serum and then determined transcriptional profiles by microarray hybridization. We identified and verified important downstream target genes by single gene analysis and qRT-PCR and then identified important biological processes by Gene Set Analysis using Biological Process Gene Sets from the Gene Ontology Consortium. We found that CHF1/Hey2 suppresses pathways involved in water transport, adenylate cyclase activity, embryonic eye morphogenesis, gut development and fluid transport after serum stimulation. Genes involved in protein dephosphorylation, demonstrate increased expression in myocytes overexpressing CHF1/Hey2, independent of serum treatment. Genes overexpressed prior to serum treatment are involved in regulation of transcription factor activity, nuclear protein export and steroid hormone receptor signaling. Genes overexpressed after serum treatment are involved in autophagy, apoptosis and mitochondrial biogenesis. Show less

We have previously found that CHF1/Hey2 prevents the development of phenylephrine-induced cardiac hypertrophy. To determine the role of CHF1/Hey2 in pressure overload hypertrophy, we performed ascending aortic banding on wild-type and transgenic mice overexpressing CHF1/Hey2 in the myocardium. We found that both wild-type and transgenic mice developed increased ventricular weight to body weight ratios 1 week after aortic banding. Wild-type mice also developed decreased fractional shortening after 1 week when compared to preoperative echocardiograms and sham-operated controls. Transgenic mice, in comparison, demonstrated preserved fractional shortening. Histological examination of explanted heart tissue demonstrated extensive fibrosis in wild-type hearts, but minimal fibrosis in transgenic hearts. TUNEL staining demonstrated increased apoptosis in the wild-type hearts but not in the transgenic hearts. Exposure of cultured neonatal myocytes from wild-type and transgenic animals to hydrogen peroxide, a potent inducer of apoptosis, demonstrated increased apoptosis in the wild-type cells. Gene Set Analysis of microarray data from wild-type and transgenic hearts 1 week after banding revealed suppression and activation of multiple pathways involving apoptosis, cell signaling, and biosynthesis. These findings demonstrate that CHF1/Hey2 promotes physiological over pathological hypertrophy through suppression of apoptosis and regulation of multiple transcriptional pathways. These findings also suggest that CHF1/Hey2 and its downstream pathways provide a variety of targets for novel heart failure drug discovery, and that genetic polymorphisms in CHF1/Hey2 may affect susceptibility to hypertrophy and heart failure. Show less