Search

Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim to elucidate the role of DIO2, a member of the fetal-gene-program, in pluripotent stem cell (PSC)-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age, and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human hPSC-line with a DIO2 knockdown was made using a short harpin sequence. Firstly, we showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for the tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of the fetal-gene-program. Secondly, silencing DIO2 resulted in an increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Summarizing, we identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes.

Background: The cardiovascular system and central nervous system are known to influence each other. Accordingly, neurological changes may occur after myocardial infarction (MI), which may be mediated by neuroinflammation. We investigated tumor necrosis factor alpha (TNF-α) and microglia activation in post-MI neuroinflammation. Materials and Methods: MI or sham surgery was induced in 28 male mice. Two weeks later, we performed echocardiography and dissected the brains for the western blot on TNF-α and its receptors (n = 10) or immunohistochemical stainings for microglia, doublecortin X (DCX), and TNF-α (n = 18). Plasma was collected for the measurement of circulatory cytokines. Results: The MI mice had an average infarct size of 38% of the left ventricle, heart failure was confirmed by decreased fractional shortening and increased lung weight. Plasma cytokine levels were unaltered. In brains of MI mice, there was a higher expression of TNF-α precursor protein, with trends for higher TNF-R1 and lower TNF-R2 expression. Furthermore, MI mice had more activated microglia in the inner blade of the dentate gyrus of the hippocampus. The amount of neurogenesis measured by DCX staining was unaltered. Conclusions: Our mouse model of MI showed signs of persistent neuroinflammation as indicated by raised levels of TNF-α precursor protein and an increased number of activated microglia in the hippocampus. The extent to which these neuroinflammatory hallmarks influence central nervous system functioning remain to be determined.

Cardiac thyroid-hormone signaling is a critical determinant of cellular metabolism and function in health and disease. A local hypothyroid condition within the failing heart in rodents has been associated with the re-expression of the fetally expressed thyroid-hormone inactivating enzyme deiodinase type III (Dio3). While this enzyme emerges as a common denominator in the development of heart failure, the mechanism underlying its regulation remains largely unclear. In the present study, we investigated the involvement of microRNAs (miRNAs) in the regulation of Dio3 mRNA expression in the remodeling left ventricle of the mouse heart following myocardial infarction (MI). In silico analysis indicated that of the miRNAs that are differentially expressed in the post-MI heart, miR-214 has the highest potential to target Dio3 mRNA. In accordance, a luciferase reporter assay including the full length 3’UTR of mouse Dio3 mRNA, showed a 30% suppression of luciferase activity by miR-214. In the post-MI mouse heart, miR-214 and Dio3 protein were shown to be co-expressed in cardiomyocytes, while time-course analysis revealed that Dio3 mRNA expression precedes miR-214 expression in the post-MI left ventricle. This suggests that a Dio3-induced decrease of T3 levels is involved in the induction of miR-214, which was supported by the finding that cardiac miR-214 expression is down regulated by T3 in mice. In vitro analysis of human DIO3 mRNA furthermore showed that miR-214 is able to suppress both mRNA and protein expression. Dio3 mRNA is a target of miR-214 and the Dio3-dependent stimulation of miR-214 expression in post-MI cardiomyocytes support the involvement of a negative feedback mechanism regulating Dio3 expression.

Cardiomyocyte size in the healthy heart is in part determined by the level of circulating thyroid hormone (TH). Higher levels of TH induce ventricular hypertrophy, primarily in response to an increase in hemodynamic load. Normal cardiac function is maintained in this form of hypertrophy, whereas progressive contractile dysfunction is a hallmark of pathological hypertrophy. MicroRNAs (miRNAs) are important modulators of signal-transduction pathways driving adverse remodeling. Because little is known about the involvement of miRNAs in cardiac TH action and hypertrophy, we examined the miRNA expression profile of the hypertrophied left ventricle (LV) using a mouse model of TH-induced cardiac hypertrophy. C57Bl/6J mice were rendered hypothyroid by treatment with propylthiouracil and were subsequently treated for three days with TH (T3) or saline. T3-treatment increased LV weight by 38% (p2-fold change (p

Sea‐level rise (SLR) will cause coastal groundwater to rise in many coastal urban environments. Inundation of contaminated soils by groundwater rise (GWR) will alter the physical, biological, and geochemical conditions that influence the fate and transport of existing contaminants. These transformed products can be more toxic and/or more mobile under future conditions driven by SLR and GWR. We reviewed the vulnerability of contaminated sites to GWR in a US national database and in a case comparison with the San Francisco Bay region to estimate the risk of rising groundwater to human and ecosystem health. The results show that 326 sites in the US Superfund program may be vulnerable to changes in groundwater depth or flow direction as a result of SLR, representing 18.1 million hectares of contaminated land. In the San Francisco Bay Area, we found that GWR is predicted to impact twice as much land area as inundation from SLR, and 5,282 additional state‐managed sites of contamination may be vulnerable to inundation from GWR in a 1.0 m SLR scenario. Increases of only a few centimeters of elevation can mobilize soil contaminants, alter flow directions in a heterogeneous urban environment with underground pipes and utility trenches, and result in new exposure pathways. Pumping for flood protection will elevate the saltwater interface, changing groundwater salinity and mobilizing metals in soil. Socially vulnerable communities are disproportionately exposed to this risk at both the national scale and in a regional comparison with the San Francisco Bay Area. Plain Language Summary: We estimated the number of sites with known contamination in the US Superfund program at the national scale and found 326 Superfund sites that may be exposed to inundation from below as rising sea levels push groundwater higher along the coast. California, North Carolina, Virginia, and New York have the largest area of federally managed contaminated land that may be exposed. Thousands of additional sites are managed by state agencies. We conducted a comparison in the San Francisco Bay Area that included state‐managed sites. We found that more than 5,000 sites in the San Francisco region may be exposed to rising groundwater with sea‐level rise (SLR) of 1.0 m, including 1,480 open sites, and an additional 3,817 closed sites that may contain residual contaminants. If the ratio of Superfund to state‐managed sites in this region (1:406) holds, the number of at‐risk contaminated sites nationally may be more than 132,000. Low‐income residents and people of color are disproportionately represented near these sites and therefore may face higher risks. Additional sub‐regional research is urgently needed to understand these exposures. Interactions will occur between the salinity of rising coastal groundwater and shallow pumping, affecting infrastructure and building foundations. Adaptation plans must consider rising groundwater to avoid widespread failures. Key Points: Rising sea levels will cause rising groundwater to inundate some coastal contaminated sites, mobilizing pollutants and causing corrosionWe found 326 Superfund sites that may be at risk nationally, and more than 5,000 state managed sites in a San Francisco Bay area comparisonSocially vulnerable communities are disproportionately exposed to this hazard, with potential impacts on indoor air, foundations and infrastructure [ABSTRACT FROM AUTHOR]