Biology subjects

Archer, S. L.

Publications and source records attributed to Archer, S. L..

4 recordsLinked to original sources

bioRxiv2023

Efficacy of Drpitor1a, a Dynamin-Related Protein 1 inhibitor, in Pulmonary Arterial Hypertension

RationaleDynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes pulmonary arterial hypertension (PAH). We developed a Drp1 inhibitor, Drpitor1a, and tested its ability to regress PAH. ObjectivesAssess Drpitor1as efficacy and toxicity in: a)normal and PAH human PASMC (hPASMC); b)normal rats versus rats with established monocrotaline (MCT)-induced PAH. MethodsDrpitor1as effects on recombinant and endogenous Drp1-GTPase activity, mitochondrial fission, and cell proliferation were studied in hPASMCs (normal=3; PAH=5). Drpitor1as pharmacokinetics and tissue concentrations were measured (n=3 rats/sex). In a pilot study (n=3-4/sex/dose), Drpitor1a (1mg/kg/48-hours, intravenous) reduced adverse PA remodeling only in females. Consequently, we compared Drpitor1a to vehicle in normal (n=6 versus 8) and MCT-PAH (n=9 and 11) females, respectively. Drpitor1a treatment began 17-days post-MCT with echocardiography and cardiac catheterization performed 28-29 days post-MCT. ResultsDrpitor1a inhibited recombinant and endogenous Drp1 GTPase activity, which was increased in PAH hPASMC. Drpitor1a inhibited mitochondrial fission and proliferation and induced apoptosis, in PAH hPASMC but not normal hPASMC. Drpitor1a tissue levels were higher in female versus male RVs. In MCT-PAH females, Drpitor1a regressed PA obstruction, lowered pulmonary vascular resistance, and improved RV function, without hematologic, renal, or hepatic toxicity. ConclusionsDrpitor1a inhibits Drp1 GTPase, reduces mitochondrial fission, and inhibits cell proliferation in PAH hPASMC. Drpitor1a caused no toxicity in MCT-PAH and had no significant effect on normal rats or hPASMCs. Drpitor1a is a potential PAH therapeutic which displays an interesting therapeutic sexual dimorphism.

pharmacology and toxicology↗

bioRxiv2023

Circular RNA profiling identifies circ5078 as a BMPR2-derived regulator of endothelial translation

Germline loss-of-function BMPR2 mutations are the leading genetic cause of pulmonary arterial hypertension (PAH) and are strongly linked to aberrant endothelial proliferation and impaired translational stress responses. While these effects are generally attributed to a loss of the type-II bone morphogenetic protein receptor (BMPR-II), we used circular RNA profiling to identify circ5078 as a new functional RNA derived from exon 12 of the BMPR2 gene. circ5078 and linear BMPR2 mRNA exert opposing effects on endothelial proliferation and stress granule formation, driving impaired stress responses in PAH patient-derived endothelial cells that are deficient in linear BMPR2 transcripts, but not circ5078. Rebalancing circular to linear transcript abundance by circ5078 depletion rescued stress granule formation in patient-derived endothelial cells, independent of BMPR-II protein levels. Polysome analysis demonstrated a reduction in free ribosomal subunits with the depletion of either linear or circular BMPR2 transcripts, and an accumulation of 80S monosomes exclusively with linear BMPR2 mRNA loss. These effects did not impact global protein synthesis or stress-induced eIF2 phosphorylation, but did alter the translational efficiency of multiple genes, including a group of nuclear encoded, mitochondrial ribosome proteins that were translationally enhanced with circ5078 silencing. Endothelial circ5078 depletion increased the efficiency of oxidative metabolism while reducing mitochondrial spare capacity, providing a potential link between mitochondrial function, proliferation and translational stress responses. Together, these findings reveal interdependent roles for linear and circular BMPR2 transcripts as functional contributors to the endothelial phenotype of PAH.

molecular biology↗

bioRxiv2023

The Herpes Simplex Virus pUL16 and pUL21 Proteins Prevent Capsids from Docking at Nuclear Pore Complexes

After entry into cells, herpes simplex virus (HSV) nucleocapsids dock at nuclear pore complexes (NPCs) through which viral genomes are released into the nucleoplasm where viral gene expression, genome replication, and early steps in virion assembly take place. After their assembly, nucleocapsids are translocated to the cytoplasm for final virion maturation. Nascent cytoplasmic nucleocapsids are prevented from binding to NPCs and delivering their genomes to the nucleus from which they emerged, but how this is accomplished is not understood. Here we report that HSV pUL16 and pUL21 deletion mutants accumulate empty capsids at the cytoplasmic face of NPCs late in infection. Additionally, prior expression of pUL16 and pUL21 prevented incoming nucleocapsids from docking at NPCs, delivering their genomes to the nucleus and initiating viral gene expression. Both pUL16 and pUL21 localized to the cytoplasmic face of the nuclear envelope, placing them in an appropriate location to interfere with nucleocapsid/NPC interactions.

microbiology↗

bioRxiv2023

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

biochemistry↗