Biology subjects

Garrett, M. R.

Publications and source records attributed to Garrett, M. R..

3 recordsLinked to original sources

bioRxiv2025

Pregnancy-Dependent Cardioprotection via GPER Activation in Dahl Salt-Sensitive Rats

BackgroundPreeclampsia is a hypertensive disorder of pregnancy that affects multiple organs, including the heart, increasing long-term cardiovascular risks for both the mother and offspring. While the G protein-coupled estrogen receptor (GPER) has cardioprotective effects, its role in pregnancy-associated cardiac dysfunction, particularly in chronic hypertension, remains unclear, given the significant physiological adaptations that occur during pregnancy, including hormonal fluctuations and hemodynamic changes. This study investigated whether LNS8801, a selective and orally bioavailable GPER agonist, could improve cardiac function in virgin and pregnant Dahl salt-sensitive (SS/Jr) rats, a model of chronic hypertension exacerbated by pregnancy. MethodsFemale Dahl SS/Jr rats, both virgin and pregnant, were randomized into four groups: Virgin + Vehicle, Virgin + LNS8801, Pregnant + Vehicle, and Pregnant + LNS8801. LNS8801 (800 {micro}g/kg/day, given orally) was administered in pregnant rats from gestational day (GD) 9 to 20 and for an equivalent period in virgin controls. Cardiac function was assessed via echocardiography, including speckle-tracking strain analysis and conventional systolic and diastolic parameters. Mean arterial pressure and proteinuria were also measured. ResultsLNS8801 significantly improved cardiac function in pregnant Dahl SS/Jr rats, enhancing global longitudinal, circumferential, and radial strain, as well as increasing systolic function. Additionally, LNS8801 enhanced diastolic function, improving left ventricular compliance (E/A ratio) and early mitral annular velocity (e'), while reducing left ventricular filling pressures (E/e' ratio). In contrast, LNS8801 had no significant effects on cardiac function and blood pressure in virgin Dahl SS/Jr rats, suggesting that pregnancy-related adaptations may enhance GPER-mediated cardioprotection. LNS8801 treatment significantly reduced proteinuria in both virgin and pregnant rats, indicating a pregnancy-independent renal protective effect. ConclusionThis study highlights the importance of pregnancy-specific adaptations in shaping the cardiovascular effects of GPER activation. While LNS8801 demonstrated cardioprotective and antihypertensive benefits in pregnant Dahl SS/Jr rats, its effects were absent in virgin animals, underscoring the influence of the physiological and hormonal environment on GPER-mediated responses. These findings provide a foundation for further exploration of GPER as a therapeutic target for pregnancy-associated cardiovascular dysfunction and preeclampsia, reinforcing the need for pregnancy-specific approaches in drug development.

pharmacology and toxicology↗

bioRxiv2024

Removal of the catalytic subunit of DNA-protein kinase in the proximal tubules promotes DNA and tubular damage during kidney injury

Tubular epithelial cell damage can be repaired through a series of complex signaling pathways. An early event in many forms of tubular damage is the observation of DNA damage, which can be repaired by specific pathways depending upon the type of genomic alteration.. In this study, we report that the catalytic subunit of DNA protein kinase (DNA-PKcs), a central DNA repair enzyme involved in sensing DNA damage and performing double stranded DNA break repair, plays an important role in the extent of tubular epithelial cell damage following exposure to injurious acute and chronic stimuli. Selective loss of DNA-PKcs in the proximal tubules led to increased markers of kidney dysfunction, DNA damage, and tubular epithelial cell injury in multiple models of acute kidney injury, specifically bilateral renal ischemia-reperfusion injury and single dose of cisplatin (15 mg/kg IP). In contrast, in a mouse model of kidney fibrosis and chronic kidney disease (UUO),the protective effects of DNA-PKcs was not as obvious histologically from the tissue sections. In the absence of proximal tubular DNA-PKcs, there was reduced levels of fibrotic markers, -SMA and fibronectin, which suggests that there may be a biphasic role of DNA-PKcs depending upon the conditions exerted upon the kidney. In conclusion, this study demonstrates that the catalytic subunit of DNA-PKcs plays a context-dependent role in the kidney to reduce DNA damage during exposure to various types of acute, but not chronic forms of injurious stimuli.

physiology↗

bioRxiv2024

Impact of variants and vaccination on nasal immunity across three waves of SARS-CoV-2

SARS-CoV-2 infection and COVID-19 disease vary with respect to viral variant and host vaccination status. However, how vaccines, emergent variants, and their intersection shift host responses in the human nasal mucosa remains uncharacterized. We and others have shown during the first SARS-CoV-2 wave that a muted nasal epithelial interferon response at the site of infection underlies severe COVID-19. We sought to further understand how upper airway cell subsets and states associate with COVID-19 phenotypes across viral variants and vaccination. Here, we integrated new single-cell RNA-sequencing (scRNA-seq) data from nasopharyngeal swabs collected from 67 adult participants during the Delta and Omicron waves with data from 45 participants collected during the original (Ancestral) wave in our prior study. By characterizing detailed cellular states during infection, we identified changes in epithelial and immune cells that are both unique and shared across variants and vaccination status. By defining SARS-CoV-2 RNA+ cells for each variant, we found that Delta samples had a marked increase in the abundance of viral RNA+ cells. Despite this dramatic increase in viral RNA+ cells in Delta cases, the nasal cellular compositions of Delta and Omicron exhibit greater similarity, driven partly by myeloid subsets, than the Ancestral landscapes associated with specialized epithelial subsets. We found that vaccination prior to infection was surprisingly associated with nasal macrophage recruitment and activation rather than adaptive immune cell signatures. While patients with severe disease caused by Ancestral or Delta variants had muted interferon responses, Omicron-infected patients had equivalent interferon responses regardless of disease severity. Our study defines the evolution of cellular targets and signatures of disease severity in the upper respiratory tract across SARS-CoV-2 variants, and suggests that intramuscular vaccines shape myeloid responses in the nasal mucosa upon SARS-CoV-2 infection.

immunology↗