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Circulation research [journal]
- Control of Very-Low Density Lipoprotein Secretion by N-Ethylmaleimide-Sensitive Factor and miR-33. [JOURNAL ARTICLE]
- Circ Res 2014 Apr 21.
Several reports suggest that antisense oligonucleotides against miR-33 might reduce cardiovascular risk in patients by accelerating the reverse cholesterol transport pathway. However, conflicting reports exist regarding the impact of anti-miR-33 therapy on the levels of very low-density lipoprotein-triglycerides (VLDL-TAG).We test the hypothesis that miR-33 controls hepatic VLDL-TAG secretion.Using therapeutic silencing of miR-33 and adenoviral overexpression of miR-33, we show that miR-33 limits hepatic secretion of VLDL-TAG by targeting N-ethylmaleimide-sensitive factor (NSF), both in vivo and in primary hepatocytes. We identify conserved sequences in the 3'UTR of NSF as miR-33 responsive elements, and show that Nsf is specifically recruited to the RNA-Induced Silencing Complex (RISC) following induction of miR-33. In pulse-chase experiments, either miR-33 overexpression or knock-down of Nsf lead to decreased secretion of apoproteins and TAG in primary hepatocytes, compared to control cells. Importantly, Nsf rescues miR-33-dependent reduced secretion. Finally, we show that overexpression of Nsf in vivo increases global hepatic secretion and raises plasma VLDL-TAG.Together, our data reveal key roles for the miR-33-NSF axis during hepatic secretion, and suggest that caution should be taken with anti-miR-33-based therapies since they might raise pro-atherogenic VLDL-TAG levels.
- HIC2 is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region. [JOURNAL ARTICLE]
- Circ Res 2014 Apr 18.
22q11 deletion syndrome arises from recombination between low copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack extra-cardiac features of the syndrome suggesting that a second haploinsufficient gene maps to this interval.The transcription factor HIC2 is lost in most distal deletions as well as a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease.We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5 while the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. Magnetic resonance imaging demonstrated a ventricular septal defect with overriding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages. Microarray analysis revealed increased expression of Bmp10.Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggests HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome.
- Fli1 Acts Downstream of Etv2 to Govern Cell Survival and Vascular Homeostasis via Positive Autoregulation. [JOURNAL ARTICLE]
- Circ Res 2014 Apr 11.
Cardiovascular health depends on proper development and integrity of blood vessels. Etv2 (Ets variant 2), a member of the E26 transforming specific (ETS) family of transcription factors, is essential to initiate a transcriptional program leading to vascular morphogenesis in early mouse embryos. However, endothelial expression of the Etv2 gene ceases at mid-gestation; therefore, vascular development past this stage must continue independent of Etv2.To identify molecular mechanisms underlying transcriptional regulation of vascular morphogenesis and homeostasis in the absence of Etv2.Utilizing loss- and gain-of-function strategies and a series of molecular techniques, we identify Fli1 (Friend leukemia integration 1), another ETS family transcription factor, as a downstream target of Etv2. We demonstrate that Etv2 binds to conserved Ets-binding sites (EBSs) within the promoter region of the Fli1 gene and governs Fli1 expression. Importantly, in the absence of Etv2 at mid-gestation, binding of Etv2 at EBSs in the Fli1 promoter is replaced by Fli1 protein itself, sustaining expression of Fli1 as well as selective Etv2-regulated endothelial genes to promote endothelial cell survival and vascular integrity. Consistent with this, we report that Fli1 binds to the conserved EBSs within promoter and enhancer regions of other Etv2-regulated endothelial genes, including Tie2, to control their expression at and beyond mid-gestation.We have identified a novel positive feed-forward regulatory loop in which Etv2 activates expression of genes involved in vasculogenesis, including Fli1. Once the program is activated in early embryos, Fli1 then takes over to sustain the process in the absence of Etv2.
- Correction. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):e34.
- Unique metabolic features of stem cells, cardiomyocytes, and their progenitors. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):1346-60.
Recently, growing attention has been directed toward stem cell metabolism, with the key observation that the plasticity of stem cells also reflects the plasticity of their energy substrate metabolism. There seems to be a clear link between the self-renewal state of stem cells, in which cells proliferate without differentiation, and the activity of specific metabolic pathways. Differentiation is accompanied by a shift from anaerobic glycolysis to mitochondrial respiration. This metabolic switch of differentiating stem cells is required to cover the energy demands of the different organ-specific cell types. Among other metabolic signatures, amino acid and carbohydrate metabolism is most prominent in undifferentiated embryonic stem cells, whereas the fatty acid metabolic signature is unique in cardiomyocytes derived from embryonic stem cells. Identifying the specific metabolic pathways involved in pluripotency and differentiation is critical for further progress in the field of developmental biology and regenerative medicine. The recently generated knowledge on metabolic key processes may help to generate mature stem cell-derived somatic cells for therapeutic applications without the requirement of genetic manipulation. In the present review, the literature about metabolic features of stem cells and their cardiovascular cell derivatives as well as the specific metabolic gene signatures differentiating between stem and differentiated cells are summarized and discussed.
- Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):1328-45.
Coronary artery disease with associated myocardial infarction continues to be a major cause of death and morbidity around the world, despite significant advances in therapy. Patients who have large myocardial infarctions are at highest risk for progressive heart failure and death, and cell-based therapies offer new hope for these patients. A recently discovered cell source for cardiac repair has emerged as a result of a breakthrough reprogramming somatic cells to induced pluripotent stem cells (iPSCs). The iPSCs can proliferate indefinitely in culture and can differentiate into cardiac lineages, including cardiomyocytes, smooth muscle cells, endothelial cells, and cardiac progenitors. Thus, large quantities of desired cell products can be generated without being limited by cellular senescence. The iPSCs can be obtained from patients to allow autologous therapy or, alternatively, banks of human leukocyte antigen diverse iPSCs are possible for allogeneic therapy. Preclinical animal studies using a variety of cell preparations generated from iPSCs have shown evidence of cardiac repair. Methodology for the production of clinical grade products from human iPSCs is in place. Ongoing studies for the safety of various iPSC preparations with regard to the risk of tumor formation, immune rejection, induction of arrhythmias, and formation of stable cardiac grafts are needed as the field advances toward the first-in-man trials of iPSCs after myocardial infarction.
- Role of RyR2 Phosphorylation in Heart Failure and Arrhythmias: Protein Kinase A-Mediated Hyperphosphorylation of the Ryanodine Receptor at Serine 2808 Does Not Alter Cardiac Contractility or Cause Heart Failure and Arrhythmias. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):1320-7.
This Controversies in Research article discusses the hypothesis that protein kinase A (PKA)-mediated phosphorylation of the Ryanodine Receptor (RyR) at a single serine (RyRS2808) is essential for normal sympathetic regulation of cardiac myocyte contractility and is responsible for the disturbed Ca(2+) regulation that underlies depressed contractility in heart failure. Studies supporting this hypothesis have associated hyperphosphorylation of RyRS2808 and heart failure progression in animals and humans and have shown that a phosphorylation defective RyR mutant mouse (RyRS2808A) does not respond normally to sympathetic agonists and does not exhibit heart failure symptoms after myocardial infarction. Studies to confirm and extend these ideas have failed to support the original data. Experiments from many different laboratories have convincingly shown that PKA-mediated RyRS2808 phosphorylation does not play any significant role in the normal sympathetic regulation of sarcoplasmic reticulum Ca2+ release or cardiac contractility. Hearts and myocytes from RyRS2808A mice have been shown to respond normally to sympathetic agonists, and to increase Ca(2+) influx, Ca(2+) transients, and Ca(2+) efflux. Although the RyR is involved in heart failure-related Ca(2+) disturbances, this results from Ca(2+)-calmodulin kinase II and reactive oxygen species-mediated regulation rather than by RyR2808 phosphorylation. Also, a new study has shown that RyRS2808A mice are not protected from myocardial infarction. Collectively, there is now a clear consensus in the published literature showing that dysregulated RyRs contribute to the altered Ca(2+) regulatory phenotype of the failing heart, but PKA-mediated phosphorylation of RyRS2808 has little or no role in these alterations.
- Role of RyR2 Phosphorylation in Heart Failure and Arrhythmias: Controversies Around Ryanodine Receptor Phosphorylation in Cardiac Disease. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):1311-9.
Cardiac ryanodine receptor type 2 plays a key role in excitation-contraction coupling. The ryanodine receptor type 2 channel protein is modulated by various post-translational modifications, including phosphorylation by protein kinase A and Ca(2+)/calmodulin protein kinase II. Despite extensive research in this area, the functional effects of ryanodine receptor type 2 phosphorylation remain disputed. In particular, the potential involvement of increased ryanodine receptor type 2 phosphorylation in the pathogenesis of heart failure and arrhythmias remains a controversial area, which is discussed in this review article.
- How to write a successful grant application and research paper. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):1231-4.
- Metabolic flux as a predictor of heart failure prognosis. [Journal Article]
- Circ Res 2014 Apr 11; 114(8):1228-30.