Biology subjects

Kaul, S.

Publications and source records attributed to Kaul, S..

10 recordsLinked to original sources

bioRxiv2026

Impact of GPR39 Inhibition on Tissue Oxygen Tension in Acute Myocardial Infarction: Modeling Using an Indirect Response Pharmacokinetics/Pharmacodynamics Approach

In pre-clinal studies, VC108, a novel GPR39 inhibitor, increased myocardial O2 tension (mpO2) during different phases of acute myocardial infarction (AMI). The purpose of this work was to investigate the temporal effects of VC108 on mpO2 using a novel population PK/PD model developed from preclinical data using healthy animals and animals subjected to AMI protocols. PK/PD simulations were then performed to explore mpO2 dynamic in untested experimental scenarios. VC108 PK data fitted well to a two-compartment model with linear elimination with body weight, sex, and nominal dose identified as significant covariates influencing clearance and/or central compartment volume. Applying indirect effect model principles for representing mpO2 flux, a structural population PK/PD model was developed to capture mpO2 dynamics during different AMI phases: before and during coronary occlusion and after reperfusion. The model successfully captured basal mpO2 homeostasis, ischemic decline, and reperfusion overshoot, while quantifying the contribution of VC108 to collateral blood flow and functional recovery. Dose response relationships were simulated to measure the effect of different VC108 dose levels on permanent damage, i.e. a reduction in mpO2 at steady state after AMI. The probability of remaining below predefined damage thresholds (mpO2 reduction of 5% to 20%) increased with dose in both sexes, with females consistently achieving greater protection that plateaued around 1 mg/kg of VC108 for higher permanent damage. This model represents a valuable tool to describe, for the first time, VC108 efficacy data and pharmacokinetics with ischemia/reperfusion dynamics and quantify its effect in untested dose levels.

pharmacology and toxicology↗

bioRxiv2026

Deletion of GPR39 Prevents Pulmonary Arterial Hypertension by Attenuating Hypoxia-Induced Aberrant Signaling

Pulmonary arterial hypertension (PAH) is a devastating disease with poor outcome affecting relatively young subjects. The arachidonic acid (AA) metabolite, 15-hydroxyeicosatetraenoic acid (15-HETE), has been implicated in the pathogenesis of hypoxia-induced PAH. We tested the hypothesis that genetic deletion of GPR39, the target receptor for 15-HETE, will attenuate PAH. We subjected wild-type (WT) and GPR39 KO to 4 weeks of hypoxia versus normoxia, after which right ventricular and systemic hemodynamics were measured. Immunohistochemistry of lung was performed for pulmonary arteriolar thickness as well as capillary and pericyte density. Lung tissue was also analyzed for AA and 15-HETE levels as well as signaling events (mRNA and protein levels) downtream of GPR39 activation. Unlike WT mice, GPR39 KO mice did not develop PAH. They also exhibited markedly less pulmonary ateriolar remodeling and greater pulmonary capillary density. mRNA expression of genes in the Gq, Gsand G12/13 pathways were upregulated in the WT mice while GPR39 KO hypoxic showed no change in these genes. WT and not GPR39 KO hypoxic mice exhibited enhanced AKT phosphorylation. Downstream of the phosphatidylinositol 3-kinase-AKT pathway, endothelial nitric oxide synthetase was upregulated in both WT hypoxia and GPR39 KO hypoxia mice, while sonic hedgehog was upregulated only in WT hypoxia mice. We conclude that hypoxia-induced aberrant signaling is markedly attenuated with genetic deletion of GPR39, which is associated with less pulmonary arteriolar remodeling and greater capillary density, thus preventing PAH. These results suggest that pharmacological inhibition of GPR39 may offer a novel treatment for PAH.

physiology↗

bioRxiv2026

Selective Pharmacological Blockade of GPR39 Markedly Reduces No Reflow and Infarct Volumes in a Rat Model of Acute Myocardial Infarction

Our aim was to determine whether selective pharmacological blockade of GPR39 by the novel drug, VC108, reduces no reflow (NRV) and infarct (INV) volumes during acute myocardial infarction (AMI). Immuocytochemistry and qPCR of isolated rat cardiac cells as well as immunohistochemistry and western blot of rat myocardium was performed for presence of GPR39. Rats underwent 1 h of coronary occlusion and 1 h of reperfusion. Groups 1 and 2 animals received drug/vehicle prior to or during coronary occlusion. Groups 3 and 4 received drug/vehicle 5 min prior to or 30 min after reperfusion. Readouts also included tissue pO2, hemodynamics, and wall thickening. In Groups 5 and 6 animals, drug was injected for measurement of plasma and tissue levels. Immunocytochemistry and qPCR of cells and immunohistochemistry and western blot of tissue revealed GPR39 expression in all cardiac cells analyzed as well as entire myocardial tissue. There was marked reduction in NRV and INV in groups 1 and 3 animals where both were measured and in Group 2 where INV was measured. In contrast, Group 4 animals failed to show reduction in NRV and INV with the drug. The reduction in NRV in all animals was associated with higher tissue pO2 in VC108 compared to vehicle treated animals. Similar results were obtained for INV in only in Group 2 animals. In Group 3 animals direct cardiomyocyte effect of VC108 was seen in myocardium as evidenced by reduced necrosis and apoptosis. We conclude that VC108 is very effective in reducing INV and NRV in an AMI model when given before coronary occlusion or just prior to reperfusion (the latter being clinically more relevant) both in male and female rats. This effect is not seen after reperfusion. VC108 acts by blocking GPR39, resulting in vasodilation through pericyte and VSMC relaxation. It also directly protects cardiomyocytes by preventing downstream effects of GPR39 stimulation. New and NoteworthyGPR39 is the receptor for 15-HETE, which is a vasoconstrictor with direct cardiomyocyte detrimental effects. Pharmacological inhibition of GPR39 by a novel inhibitor, VC108, reduces coronary no reflow after acute myocardial infarction by relaxing contracted pericytes surrounding capillaries, whereby increasing oxygen delivery. GPR39 inhibition also reduces necrosis and ferroptosis by interrupting aberrant downstream signaling responsible for cell death. Hence, pharmacological inhibition of GPR39 by VC108 offers a novel treatment of acute myocardial infarction. Graphical AbstractProposed mechanism of action of VC108 when given prior to and during coronary occlusion based on our results. The drug inhibits the action of the vasoconstrictor, 15-HETE, on GPR39. This causes vasodilation by relaxing contracted pericytes and increasing capillary perfusion, resulting in increased tissue pO2 and reduction in no reflow (left side). When tissue pO2 is not associated with necrosis, GPR39 inhibition by VC108 directly affects cardiomyocytes by inhibiting downstream signaling of GPR39 present in cardiomyocytes that can lead to cell injury and death. Hence, less necrosis and apoptosis are noted in VC108 versus vehicle treated animals. Created in https://BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/699339v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1058995org.highwire.dtl.DTLVardef@8bc0ceorg.highwire.dtl.DTLVardef@11f44e0org.highwire.dtl.DTLVardef@1e2e337_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

15-Hydroxyeicosatetraenoic Acid and GPR39 Together Orchestrate Coronary Autoregulation: A Comprehensive Metabolomic Analysis

BackgroundCoronary autoregulation is the ability of the normal heart to maintain constant coronary blood flow (CBF) over a wide range of coronary driving pressures (CDP). Despite being vital for survival, the mechanism of coronary autoregulation is unknown. We hypothesized that GPR39, present in vascular smooth muscle cells, together with its endogenous agonist 15- hydroxyeicosatetraenoic acid (15-HETE) orchestrate coronary autoregulation. MethodsWe created coronary stenoses of varying degrees in open-chest, anesthetized dogs where we measured CBF and CDP. In a subset of animals, coronary venous blood was sampled for eicosanoid, adenosine, endothelin-1, polyunsaturated fatty acids, and prostaglandins levels. Stenoses were recreated during intravenous administration of VC108, a specific GPR39 antagonist and systemic, pulmonary, and coronary hemodynamics measured. ResultsGPR39 was identified in coronary arterioles by immunohistochemistry and in heart tissue by western blot. In-vivo, 15-HETE correlated the best (r2=0.4851, p=0.0144) with CDP over the autoregulatory range using a linear mixed-effects model. Prior to administration of VC108, CBF did not change within the autoregulatory range. VC108 had no effect on systemic and pulmonary hemodynamics but increased CBF (p=0.02 versus vehicle) by decreasing coronary microvascular resistance (p=0.01 versus vehicle), indicating that GPR39 participates in control of normal coronary vascular tone. With VC108, coronary autoregulation was abolished and CBF became CDP dependent (r2=0.9562, p=0.0039). ConclusionGPR39 and its endogenous agonist 15-HETE together orchestrate coronary autoregulation when CDP is reduced. These novel findings provide a mechanism for coronary autoregulation and could direct pharmacological treatment of various coronary syndromes in humans. Clinical Perspectives What is new?The new finding from this study is that the vasoconstrictor, 15- hydroxyeicosatetraenoic acid (15-HETE), acting via the G-protein coupled receptor 39 (GPR39) participates in coronary arteriolar tone, and when perfusion pressure falls because of coronary stenosis, 15-HETE levels decrease causing vasodilation to maintain resting coronary blood flow. What are the Clinical implicationsThis mechanism, termed coronary autoregulation, causes patients with coronary artery disease to remain asymptomatic at rest until coronary stenosis is very severe. Pharmacological inhibition of GPR39 causes selective coronary vasodilation and could be used to treat coronary artery disease.

physiology↗

bioRxiv2025

Functional analysis of ligand-gated chloride channels in a cnidarian sheds light on the evolution of inhibitory signalling

{psi}-aminobutyric acid (GABA) is the predominant inhibitory transmitter in the vertebrate nervous system. Fast inhibitory signalling is mediated by type A GABA receptors (GABAARs), which form pentameric ligand-gated ion channels. While GABA is also present in plants and prokaryotes, it is unknown when it was first used for fast neuronal transmission. Cnidaria represent a sister group to all Bilateria and possess a variety of putative GABAARs, none of which has been functionally characterized. In this study, we surveyed putative inhibitory ion channel receptors from the model cnidarians Nematostella and Hydra. Phylogenetic analysis revealed a surprising complexity of these receptors. The majority formed a cnidarian-specific radiation with some receptors forming a basal clade. We functionally analyzed seven putative Nematostella GABAARs of this radiation and found that none was activated by GABA or glycine, whereas three were activated by glutamate. Using site-directed mutagenesis, we identified a lysine residue in the canonical ligand-binding pocket that is important for activation by glutamate. Our results identified a group of inhibitory ion channel receptors in Cnidaria that uses glutamate as a ligand. Moreover, they suggest that inhibitory ion channel receptors in Cnidaria massively diversified, which may have been instrumental in the evolution of complex behaviors and sensory processing by the cnidarian nervous system. This work lays the foundation for understanding the diversity and evolution of inhibitory receptors in Cnidaria and the evolution of inhibitory signalling in animal nervous systems.

neuroscience↗

bioRxiv2020

Muscle cell type diversification driven by extensive gene duplications

The evolutionary mechanisms underlying the emergence of new cell types are still unclear. Here, we address the origin and diversification of muscle cells in the diploblastic sea anemone Nematostella vectensis. We discern two fast and two slow-contracting muscle cell populations in Nematostella differing by extensive sets of paralogous genes. The regulatory gene set of the slow cnidarian muscles and the bilaterian cardiac muscle are remarkably similar. By contrast, the two fast muscles differ substantially from each other, while driving the same set of paralogous structural protein genes. Our data suggest that extensive gene duplications and co-option of individual effector modules may have played an important role in cell type diversification during metazoan evolution. One Sentence SummaryThe study of the simple sea anemone suggests a molecular mechanism for cell type evolution and morphological complexity.

developmental biology↗

bioRxiv2019

A portable, low-cost device for precise control of specimen temperature under stereomicroscopes

To facilitate precise and convenient control of biological sample temperature, we developed a low-cost device that can be used independently or with any stereomicroscope. The purpose of the device is to control the thermal environment during experimental intervals in which a specimen must be manipulated outside of an incubator, e.g. for dissection or slide-mounting in preparation for imaging. Sample temperatures can be both cooled to below and heated to above room temperatures, and stably maintained at a precision of +/- 0.1{degrees}C. To demonstrate the utility of this device, we report improved characterization of the penetrance of a short-acting temperature-sensitive allele in C. elegans embryos, and identification of the upper temperature threshold for embryonic viability for six Caenorhabditis species. By controlling the temperature environment even as a specimen is manipulated, this device offers consistency and flexibility, reduces environmental noise, and enables precision timing in experiments requiring temperature shifts.

developmental biology↗

bioRxiv2018

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.\n\nOne Sentence SummaryGPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions.

physiology↗

bioRxiv2018

PCPE2 and SR-BI Partner to Impact Accumulation of Fat in Mice

LDL receptor knockout mice (LDLr-/-) were crossed with PCPE2 knockout mice to obtain Ldlr-/-,Pcpe2-/- mice. The rationale of these studies was to examine the effects of an extracellular matrix protein, PCPE2, on fat storage in a dyslipidemic mouse model. Male Ldlr-/-, Pcpe2-/- mice were fed a Western diet for 25 weeks and their plasma triglyceride metabolism and triglyceride storage was examined. Interestingly, visceral but not subcutaneous fat pad were smaller in diet-fed Ldlr-/-,Pcpe2-/- mice compared to controls. There was no difference in the fatty acid distribution in triglyceride and cholesteryl esters (CE) among the genotypes. Ldlr-/-, Pcpe2-/- mice have higher plasma triglyceride levels and reduced lipoprotein lipase activity. Immunoprecipitation of SR-BI from cell extracts co-precipitated PCPE2 suggesting that PCPE2 and SR-BI are tightly associated. This work also showed that in the absence of PCPE2 SR-BI does not transfer CE from HDL into the cell. These results suggest that HDL, PCPE2, SR-BI, and possibly LPL are associated in an interactome that is required for CE transport into the cell. In the absence of these interactions lipid transport is significantly disrupted.

biochemistry↗

bioRxiv2017

Neuronal Patterning Of The Tubular Collar Cord Is Highly Conserved Among Enteropneusts But Dissimilar To The Chordate Neural Tube

The dorsal neural tube of chordates and the ventral nerve cord of annelids exhibit a similar molecular mediolateral architecture. Accordingly, the presence of such a complex nervous system (CNS) has been proposed for their last common ancestor. Members of Enteropneusta, a group of non-chordate deuterostomes, possess a less complex CNS including a hollow neural tube, whereby homology to its chordate counterpart remains elusive. Since the majority of data on enteropneusts stem from Saccoglossus kowalevskii, a derived direct-developer, we investigated expression of key neuronal patterning genes in the indirect-developer Balanoglossus misakiensis.\n\nThe collar cord of B. misakiensis shows anterior Six3/6 and posterior Otx + engrailed expression, in a region corresponding to the chordate brain. Neuronal Nk2.1/Nk2.2 expression is absent. Interestingly, we found median Dlx and lateral Pax6 expression domains, i.e., a condition that is reversed compared to chordates.\n\nComparative analyses reveal that CNS patterning is highly conserved among enteropneusts. BmiDlx and BmiPax6 have no corresponding expression domains in the chordate brain, which may be indicative of independent acquisition of a tubular CNS in Enteropneusta and Chordata. Moreover, mediolateral architecture varies considerably among chordates and enteropneusts, questioning the presence of a vertebrate-like patterned nervous system in the last common deuterostome ancestor.

evolutionary biology↗