Role Of Amino Acid Transporters Research Articles

Deletion of Slc1a4 Suppresses Single Mauthner Cell Axon Regeneration In Vivo through Growth-Associated Protein 43.

Spinal cord injury (SCI) is a debilitating central nervous system (CNS) disorder that leads to significant motor and sensory impairments. Given the limited regenerative capacity of adult mammalian neurons, this study presents an innovative strategy to enhance axonal regeneration and functional recovery by identifying a novel factor that markedly promotes axonal regeneration. Employing a zebrafish model with targeted single axon injury in Mauthner cells (M-cells) and utilizing the Tg (Tol056: EGFP) transgenic line for in vivo monitoring, we investigate the intrinsic mechanisms underlying axonal regeneration. This research specifically examines the role of amino acid transport, emphasizing the role of the solute carrier 1A4 amino acid transporter in axonal regeneration. Our findings demonstrate that Slc1a4 overexpression significantly enhances axonal regeneration in M-cells, whereas Slc1a4 deficiency impedes this process, which is concomitant with the downregulation of the P53/Gap43 signaling pathway. By elucidating the fundamental role of Slc1a4 in axonal regeneration and uncovering its underlying mechanisms, this study thus provides novel insights into therapeutic strategies for SCI.

Integrated metabolomic and transcriptomic analyses reveal themolecular mechanism of amino acid transport between source and sink during tea shoot development.

The weighted gene co-expression network analysis and antisense oligonucleotide-mediated transient gene silencing revealed that CsAAP6 plays an important role in amino acid transport during tea shoot development. Nitrogen transport from source to sink is crucial for tea shoot growth and quality formation. Amino acid represents the major transport form of reduced nitrogen in the phloem between source and sink, but the molecular mechanism of amino acid transport from source leaves to new shoots is not yet clear. Therefore, the composition of metabolites in phloem exudates collected by the EDTA-facilitated method was analyzed through widely targeted metabolomics. A total of 326 metabolites were identified in the phloem exudates with the richest variety of amino acids and their derivatives (93), accounting for approximately 39.13% of the total metabolites. Moreover, through targeted metabolomics, it was found that the content of glutamine, glutamic acid, and theanine was the most abundant, and gradually increased with the development of new shoots. Meanwhile, transcriptome analysis suggested that the expression of amino acid transport genes changed significantly. The WGCNA analysis identified that the expression levels of CsAVT1, CsLHTL8, and CsAAP6 genes located in the MEterquoise module were positively correlated with the content of amino acids such as glutamine, glutamic acid, and theanine in phloem exudates. Reducing the CsAAP6 in mature leaves resulted in a significant decrease in the content of glutamic acid, aspartic acid, alanine, leucine, asparagine, glutamine, and arginine in the phloem exudates, indicating that CsAAP6 played an important role in the source to sink transport of amino acids in the phloem. The research results will provide the theoretical basis and genetic resources for the improvement of nitrogen use efficiency and tea quality.

An integrative analysis of Qingfei Paidu Decoction for its anti-HCoV-229E mechanism in cold and damp environment based on the pharmacokinetics, metabolomics and molecular docking technology

BackgroundThe novel coronavirus pneumonia (COVID-19) has spread rapidly around the world. As a member against the epidemic, Qingfei Paidu Decoction (QFPDD) has been approved for the treatment of COVID-19 in China. However, its antiviral mechanism was still largely unclear. PurposeAn integrated strategy was used to explore the antiviral mechanisms of QFPDD in cold and damp environment, including pharmacokinetic (PK), network pharmacology, metabolomics and protein verification. MethodsFirstly, the pharmacokinetic study of the prototype absorbed ingredients were analyzed by UHPLC-QqQ-MS. Secondly, the metabolomics analysis of the endogenous constituents was carried out. Based on the aforementioned results, an integrated network was constructed to identify the curative components, crucial endogenous differential metabolites and related pathways. Finally, the validation tests were implemented by molecular docking and western blotting (WB). ResultsAccording to the pharmacokinetic behaviors analysis of 31 components in vivo, the flavonoids presented more longer residence time and higher exposure compared with the other compounds. The efficacy and antiviral mechanism of QFPDD were verified by the poly-pharmacology, metabolomics, molecular docking and WB. For the occurrence of metabolic disorder, the change of amino acid transporters should not be neglected. Afterward, 8 curative compounds, 6 key genes and corresponding metabolic pathways were filtered by compound-reaction-enzyme-gene network. The molecular docking verified that the active ingredients bound to the relevant targets well. ConclusionIn the present study, an in vivo comprehensive pharmacokinetic behaviors of QFPDD was analyzed for the first time. The results illustrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation and metabolic disorder to perform a corresponding therapeutic effect. Moreover, our findings highlighted the roles of amino acid transporters in the coronavirus infection situation.

Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation.

Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the POU3F4 gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a typical inner ear malformation, namely an incomplete partition of the cochlea type 3 (IP3), with or without an enlargement of the vestibular aqueduct (EVA). The pathomechanism underlying POU3F4-related deafness and the corresponding transcriptional targets are largely uncharacterized. Two male patients belonging to a Caucasian cohort with HL and EVA who presented with an IP3 were submitted to genetic analysis. Two novel sequence variants in POU3F4 were identified by Sanger sequencing. In cell-based assays, the corresponding protein variants (p.S74Afs*8 and p.C327*) showed an aberrant expression and subcellular distribution and lack of transcriptional activity. These two protein variants failed to upregulate the transcript levels of the amino acid transporter gene SLC6A20, which was identified as a novel transcriptional target of POU3F4 by RNA sequencing and RT-qPCR. Accordingly, POU3F4 silencing by siRNA resulted in downregulation of SLC6A20 in mouse embryonic fibroblasts. Moreover, we showed for the first time that SLC6A20 is expressed in the mouse cochlea, and co-localized with POU3F4 in the spiral ligament. The findings presented here point to a novel role of amino acid transporters in the inner ear and pave the way for mechanistic studies of POU3F4-related HL.

The Classification, Isolation and Function of Amino Acid Transporters in Plants

Amino acid transporters (AATs) have essential roles in transport of a broad range of amino acids, which are indispensable in plant growth and development. While many putative AATs have been identified and the complete genomic sequences of the important plants have already been completed by splicing and assembling, there is still little known about the functions of different AATs and their effects on plants. Therefore, this study mainly reviewed the role of AATs in plants from three aspects: the classification, isolation and cloning of AATs and the functional research of AATs. This review would provide useful references for the utilization of AATs in staple food crops.

The Function of Amino Acid Transporters in Plant

Amino acids are a kind of nutrient element necessary for plant growth and development. Through the participation of amino acid transporters, the transport of amino acids between aboveground and underground parts of plants and the loading of amino acids from xylem to phloem can be completed. At present, many genes encoding plant amino acid transporters have been isolated and cloned, but little is known about the functions of different amino acid transporters and their effects on plants. Therefore, this paper reviewed the role of amino acid transporters in plants from three aspects: the classification, isolation, and cloning of amino acid transporters genes and the functional research of amino acid transporters, to provide references for the utilization of amino acid transporters in plants.

EP.TH.275The role of amino acid transporters SLC1A5 and SLC3A2 in primary breast cancer in older women

Abstract Aims Breast cancer in older women has more favourable biology, compared to younger women. Increased glutamine metabolism is a hallmark of cancer. The prognostic role of amino acid transporters involved with glutamine flux, SLC1A5 and SLC3A2, has been shown in breast cancer in younger women. This study aimed to investigate the role of SLC1A5 and SLC3A2 in breast cancer in older women as possible prognostic markers. Methods Surgical specimens were obtained from an existing series of 1,758 older women (≥70 years) with primary breast cancer, treated in a single institution with long-term (37+ years) follow-up. Of this cohort, 813 had primary surgical treatment. As part of previous work, it was possible to construct good quality tissue microarrays (TMAs) in 575 cases. Immunohistochemical staining for SLC1A5 and SLC3A2 was performed. H-score was considered as a continuous variable as well as using positivity cut-offs of ≥ 45 for SLC1A5 and ≥15 for SLC3A2, using X-tile software. Association between H-score and tumour size, grade, ER status, local-recurrence-free-survival (LRFS), overall survival (OS) and breast-cancer-specific-survival (BCSS) was investigated. Results No correlation was seen between neither marker and LRFS, OS, or BCSS in older women with breast cancer. Both markers were associated with high tumour grade and negative ER status (both p < 0.001). Conclusions These findings are contrary to those found in younger women, where these amino acid transporters are associated with shorter BCSS. This may suggest that breast cancer in older women is less reliant on glutamine metabolism, which is consistent with an overall less aggressive phenotype.

Amino Acid Transporters on the Guard of Cell Genome and Epigenome.

Simple SummaryAmino acid transporters play a multifaceted role in tumor initiation, progression, and therapy resistance. They are critical to cover the high energetic and biosynthetic needs of fast-growing tumors associated with increased proliferation rates and nutrient-poor environments. Many amino acid transporters are highly expressed in tumors compared to the adjacent normal tissues, and their expression correlates with tumor progression, clinical outcome, and treatment resistance. Tumor growth is driven by epigenetic and metabolic reprogramming and is associated with excessive production of reactive oxygen species causing the damage of vital macromolecules, including DNA. This review describes the role of the amino acid transporters in maintaining tumor redox homeostasis, DNA integrity, and epigenetic landscape under stress conditions and discusses them as potential targets for tumor imaging and treatment.Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.

Quantitative Analysis of the Hydrogen Bond Interaction between Tyrosine and a Simulated Cell Membrane by SECM

The hydrogen bond between an amino acid and a negatively charged cell membrane plays significant role in amino acid transport. Electroneutral tyrosine (Tyr) was chosen, and the 3-mercaptopropionic ...

Interplay of Carbonic Anhydrase IX With Amino Acid and Acid/Base Transporters in the Hypoxic Tumor Microenvironment.

Solid tumors are challenged with a hypoxic and nutrient-deprived microenvironment. Hence, hypoxic tumor cells coordinatively increase the expression of nutrient transporters and pH regulators to adapt and meet their bioenergetic and biosynthetic demands. Carbonic Anhydrase IX (CAIX) is a membrane-bound enzyme that plays a vital role in pH regulation in the tumor microenvironment (TME). Numerous studies have established the importance of CAIX in mediating tumor progression and metastasis. To understand the mechanism of CAIX in mediating tumor progression, we performed an unbiased proteomic screen to identify the potential interactors of CAIX in the TME using the proximity-dependent biotin identification (BioID) technique. In this review, we focus on the interactors from this BioID screen that are crucial for nutrient and metabolite transport in the TME. We discuss the role of transport metabolon comprising CAIX and bicarbonate transporters in regulating intra- and extracellular pH of the tumor. We also discuss the role of amino acid transporters that are high confidence interactors of CAIX, in optimizing favorable metabolic state for tumor progression, and give our perspective on the coordinative interplay of CAIX with the amino acid transporters in the hypoxic TME.

Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation

Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1β, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored. We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis. LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor-related orphan receptor γ. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH203) and mammalian target of rapamycin (mTOR [rapamycin]). LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in γδ and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17-secreting γ4+δ4+ and CD4 T cells and dampens the release of IL-1β, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human γδ T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1β stimulation upregulates LAT1 expression and induces mTOR activation in IL-17+ γδ and TH17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23- and IL-1β-induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling. Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to controlskininflammation mediated by the IL-23/IL-1β/IL-17 axis.

The Na+/Cl--Coupled, Broad-Specific, Amino Acid Transporter SLC6A14 (ATB0,+): Emerging Roles in Multiple Diseases and Therapeutic Potential for Treatment and Diagnosis.

Amino acids are essential building blocks of all mammalian cells, and amino acid transporters play a vital role in transporting them into cells and their further distribution among the various cellular compartments. There are ~ 430 known transporters in the solute-linked carrier (SLC) gene family, divided into 52 distinct families. Eleven of these gene families contain one or more amino acid transporters. These transporters differ significantly from each other in terms of substrate specificity, ion dependence, and energetics. Given the variety of roles they fulfill in human physiology, it is not surprising that a number of diseases are associated with the malfunction of these transporters. In particular, as amino acids are critical for cell growth, survival, and proliferation, the role of amino acid transporters in cancer is gaining increasing attention in recent years. The present review primarily focuses on one particular amino acid transporter, SLC6A14 (also known as ATB0,+), with regard to its relevance to specific diseases, including cancer, and the molecular mechanisms underlying the disease-related alterations in the expression of the transporter. Furthermore, the review highlights the possible utility of this transporter in drug delivery and also its therapeutic potential for the treatment and diagnosis of cancer.

Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α

The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

The Arabidopsis paraquat resistant1 mutant accumulates leucine upon dark treatment

The Arabidopsis paraquat resistant1 (PAR1) was classified as L-type amino acid transporter 4 (LAT4) based on a phylogenetic analysis of selected genes from Saccharomyces cerevisiae, Arabidopsis thaliana (L.) Heynh, and Homo sapiens that clustered LAT4 with four other members as a LAT family in Arabidopsis. In silico analysis of the Arabidopsis LATs identified an amino acid permease domain and motifs that are common in amino acid transporters. However, their role in amino acid transport remained to be studied. A knockout mutant for PAR1/LAT4 gene, reported here as par1-5, showed significantly altered growth compared with wild type on leucine-containing growth medium. Mutant par1-5 seedlings showed reduced biomass compared with wild type on nitrate-containing Murashige and Skoog growth medium, which was further reduced when grown on medium containing nitrate and leucine. Radio-labelled leucine uptake studies using leaf protoplasts and seedlings showed increased accumulation of leucine in par1-5 mutants compared with wild type. Increased accumulation of leucine in par1-5 was detected when seedlings or protoplasts were treated in the dark prior to isotopic feeding. These studies suggest that the PAR1/LAT4 protein, in addition to its ability to mediate paraquat and polyamine transport, possess leucine transport activity that is regulated by physiological conditions such as dark induction.

Cationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites

Apicomplexans are obligate intracellular parasites that scavenge essential nutrients from their hosts via transporter proteins on their plasma membrane. The identities of the transporters that mediate amino acid uptake into apicomplexans are unknown. Here we demonstrate that members of an apicomplexan-specific protein family—the Novel Putative Transporters (NPTs)—play key roles in the uptake of cationic amino acids. We show that an NPT from Toxoplasma gondii (TgNPT1) is a selective arginine transporter that is essential for parasite survival and virulence. We also demonstrate that a homologue of TgNPT1 from the malaria parasite Plasmodium berghei (PbNPT1), shown previously to be essential for the sexual gametocyte stage of the parasite, is a cationic amino acid transporter. This reveals a role for cationic amino acid scavenging in gametocyte biology. Our study demonstrates a critical role for amino acid transporters in the survival, virulence and life cycle progression of these parasites.

Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II.

Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.

Glycinergic-Fipronil Uptake Is Mediated by an Amino Acid Carrier System and Induces the Expression of Amino Acid Transporter Genes in Ricinus communis Seedlings.

Phloem-mobile insecticides are efficient for piercing and sucking insect control. Introduction of sugar or amino acid groups to the parent compound can improve the phloem mobility of insecticides, so a glycinergic-fipronil conjugate (GlyF), 2-(3-(3-cyano-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-((trifluoromethyl)sulfinyl)-1H-pyrazole-5-yl)ureido) acetic acid, was designed and synthesized. Although the "Kleier model" predicted that this conjugate is not phloem mobile, GlyF can be continually detected during a 5 h collection of Ricinus communis phloem sap. Furthermore, an R. communis seedling cotyledon disk uptake experiment demonstrates that the uptake of GlyF is sensitive to pH, carbonyl cyanide m-chlorophenylhydrazone (CCCP), temperature, and p-chloromercuribenzenesulfonic acid (pCMBS) and is likely mediated by amino acid carrier system. To explore the roles of amino acid transporters (AATs) in GlyF uptake, a total of 62 AAT genes were identified from the R. communis genome in silico. Phylogenetic analysis revealed that AATs in R. communis were organized into the ATF (amino acid transporter) and APC (amino acid, polyaminem and choline transporter) superfamilies, with five subfamilies in ATF and two in APC. Furthermore, the expression profiles of 20 abundantly expressed AATs (cycle threshold (Ct) values <27) were analyzed at 1, 3, and 6 h after GlyF treatment by RT-qPCR. The results demonstrated that expression levels of four AAT genes, RcLHT6, RcANT15, RcProT2, and RcCAT2, were induced by the GlyF treatment in R. communis seedlings. On the basis of the observation that the expression profile of the four candidate genes is similar to the time course observation for GlyF foliar disk uptake, it is suggested that those four genes are possible candidates involved in the uptake of GlyF. These results contribute to a better understanding of the mechanism of GlyF uptake as well as phloem loading from a molecular biology perspective and facilitate functional characterization of candidate AAT genes in future studies.

Analysis of amino acid uptake and translocation in Arabidopsis with a low‐cost hydroponic system

AbstractIn soils, amino acids may be an important source of nitrogen for plants, at least in those where organic matter is not quickly degraded. The physiology of uptake of amino acids by roots was mainly studied in the 70's and 80's, before genes encoding amino acid importers were cloned in the 90's. While two families of amino acid transporters have been identified, yielding a total of about 100 genes, the role of each member is yet to be elucidated. As a tool for studying the role of amino acid transporters from Arabidopsis we set up a new hydroponic system suitable for radioisotope use. This system enables reproducible amino acid uptake by roots and estimation of the transport to the shoots of the amino acid taken up. We show that the rates of glutamine (Gln) uptake by wild‐type roots and transfer to the shoots were linear, and that other tested amino acids were translocated to the shoots with lower efficiency than Gln. A T‐DNA insertion mutant for a Gln exporter was compared to the wild‐type plants. Gln uptake and transfer were similar in both genotypes, showing that the suppression of the exporter did not affect uptake or transfer of amino acids to the shoots. The main advantage of the hydroponic system presented here is that all the materials used to grow Arabidopsis are virtually free and can therefore be discarded, a useful feature when working with radioactivity.

Abstract 102: Cd98 Modulates Atherosclerotic Plaque Morphology by Regulating Smooth Muscle Cell Proliferation via the P-38 Map Kinase Pathway

Smooth muscle cells (SMC) are known to migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. It has been shown that CD98hc, a transmembrane protein with a known role in amino acid transport and integrin signaling, is involved in proliferation and survival of various cell types including SMC. Based on these data, we hypothesized that CD98hc deficiency selectively in SMC would have pathogenic effects on atherosclerosis development and plaque composition. To test this, we utilized mice with SMC-specific deletion of the CD98hc ( CD98hc fl/fl SM22Cre + ) to determine the effects of CD98hc deficiency on SMC function in the context of atherosclerosis. We performed in vitro proliferation and survival/apoptosis assays to investigate the role of CD98hc in the proliferation and survival of primary mouse aortic vascular smooth muscle cells. We found that VSMC isolated from whole aortas of CD98hc -/- animals displayed approximately 60% reduced cell counts compared to control (41 ± 8.2% of control) after 5 days in culture. EdU assays in vivo showed a defect in the ability of CD98hc -/- SMC to proliferate, with 25% reduction in EdU-positive VSMC compared to controls (2.3 ± 0.2% vs 3 ± 0.2%). In addition, caspase-3 staining of SMC in vitro displayed a 41% increase in propensity of CD98hc -/- SMC to undergo apoptosis compared to controls (7.9 ± 0.6% vs 5.6 ± 0.5%). Furthermore, the absence of CD98hc in SMC caused a sharp increase in phosphorylated p-38, which was partially abrogated towards control levels when the cells were treated with PDGF-BB to induce proliferation. Long-term atherosclerosis study using SMC-CD98hc -/- /LDLR -/- mice showed that atherosclerotic plaque morphology was altered with increased necrotic core area (25.8 ± 1.9% vs 10.9 ± 1.6% necrotic core area per plaque area) due to a reduction in infiltration of SMC within the plaque (2.1 ± 0.4% vs 4.3 ± 0.4% SM22α positive area per plaque area) compared to control LDLR -/- mice. These data support an important role for CD98hc and its regulation of p-38 MAP kinase signaling in aortic vascular smooth muscle cell proliferation and survival. We conclude that CD98hc is critical for the formation of fibrous cap that is important in maintaining the stability of atherosclerotic plaque.

Factors controlling nutrient availability to the developing fetus in ruminants.

Inadequate delivery of nutrients results in intrauterine growth restriction (IUGR), which is a leading cause of neonatal morbidity and mortality in livestock. In ruminants, inadequate nutrition during pregnancy is often prevalent due to frequent utilization of exensive forage based grazing systems, making them highly susceptible to changes in nutrient quality and availability. Delivery of nutrients to the fetus is dependent on a number of critical factors including placental growth and development, utero-placental blood flow, nutrient availability, and placental metabolism and transport capacity. Previous findings from our laboratory and others, highlight essential roles for amino acids and their metabolites in supporting normal fetal growth and development, as well as the critical role for amino acid transporters in nutrient delivery to the fetus. The focus of this review will be on the role of maternal nutrition on placental form and function as a regulator of fetal development in ruminants.