tbuckley/cabot-search huggingface dataset:
Phenome-wide association study in 25,639 pregnant Chinese women reveals loci associated with maternal comorbidities and child health
Authors: Jintao Guo, Qiwei Guo, Taoling Zhong, Chaoqun Xu, Zhongmin Xia, Hongkun Fang, Qinwei Chen, Ying Zhou, Jieqiong Xie, Dandan Jin, You Yang, Xin Wu, Huanhuan Zhu, Ailing Hour, Xin Jin, Yulin Zhou, Qiyuan Li
Journal: Cell Genomics (2024)

Highlights•Large-scale genome-wide PheWAS in Chinese population of pregnant women and neonates•Integrating NIPT and EHR data to enhance the discovery by PheWAS•Revealing the genetic determinants of maternal-newborn comorbiditiesSummaryPhenome-wide association studies (PheWAS) have been less focused on maternal diseases and maternal-newborn comorbidities, especially in the Chinese population. To enhance our understanding of the genetic basis of these related diseases, we conducted a PheWAS on 25,639 pregnant women and 14,151 newborns in the Chinese Han population using ultra-low-coverage whole-genome sequence (ulcWGS). We identified 2,883 maternal trait-associated SNPs associated with 26 phenotypes, among which 99.5% were near established genome-wide association study (GWAS) loci. Further refinement delineated these SNPs to 442 unique trait-associated loci (TALs) predicated on linkage disequilibrium R2 > 0.8, revealing that 75.6% demonstrated pleiotropy and 50.9% were located in genes implicated in analogous phenotypes. Notably, we discovered 21 maternal SNPs associated with 35 neonatal phenotypes, including two SNPs associated with identical complications in both mothers and children. These findings underscore the importance of integrating ulcWGS data to enrich the discoveries derived from traditional PheWAS approaches.Graphical abstract
Abstract Tu143: Hsp90β Facilitates Cell Death During Acute Cardiac Ischemia/Reperfusion Injury
Authors: Richard Roberts, Halley Wisner, Sujoita Sen, Chi Lam
Journal: Circulation Research (2024)

Myocardial infarction (MI), which caused 110,000 deaths in America in 2020, occurs following a complete blockage (ischemia) in one or more of the coronary arteries. Additionally, clearing the blockage (reperfusion) causes massive cell death, resulting in permanent tissue damage in the heart. Preventing cell death in IR injury is key to improving patient outcome in this disease. Molecular chaperones have emerged as promising targets in IR injury due to their pro-survival functions. However, the role of Hsp90β, the most abundant and constitutively active chaperone, in IR injury has not been fully elucidated. Therefore, we generated a cardiac-specific Hsp90β conditional knockout (cKO) mouse model to address it. To our surprise, current preliminary results suggest that cardiac-specific Hsp90β ablation reduces myocardial damage during IR injury, as Hsp90β cKO mice showed reduced infarct size compared to control. Opening of the mitochondrial permeability transition pore (mPTP) is the major driver of necrotic cell death during early reperfusion. Isolated mitochondria from the hearts of Hsp90β cKO mice show decreased sensitivity to mPTP opening during calcium overload, suggesting that it may be one of the cardioprotective mechanisms mediated by Hsp90β ablation. The Hsp90β cKO hearts also display an anti-apoptotic shift of the BAX/BCL2 apoptotic rheostat, suggesting the heart will be more resistant to apoptotic cell death during late reperfusion phase as well. Findings from this study will help us understand the role of Hsp90β in cell death activation during IR injury. In the future, we plan to investigate the underlying protective mechanisms mediated by Hsp90β ablation.
Abstract Tu031: Immunosuppression Drug Modulation of Endothelial Cell Function
Authors: Ryan Dexheimer, David Wu, Aly Elezaby, Nazish Sayed, Ian Chen, Karim Sallam
Journal: Circulation Research (2024)

Heart transplantation is a life-saving therapy for patients with end-stage heart failure with over 4,000 transplants occurring per year. The use of immunosuppression drugs is necessary in post transplantation to prevent graft rejection. Proliferation signal inhibitors have previously been shown to effectively reduce the incidence of cardiac allograft vasculopathy (CAV) compared to calcineurin inhibitors but the differential mechanisms that drive this benefit and differences in vascular profile of immunosuppression drugs remain incompletely understood. In this study, we examined the direct effect of immunosuppressive agents on endothelial function to define cellular mechanisms that may contribute to differential vascular phenotypes. We used endothelial cells derived from human induced pluripotent stem cells (iPSCs) and treated them with calcineurin inhibitor (tacrolimus), mTOR inhibitor (sirolimus), or vehicle for 5 days with daily media changes. We examined endothelial function using scratch wound assay, tube formation assay, and LDL uptake. We also examined metabolic changes using Seahorse assay owing to metabolic changes induced by immunosuppression drugs in other organs. Our results indicate mTOR inhibitor (sirolimus) resulted in a reduction in endothelial cell proliferation and migration using the scratch wound assay and tube formation assay compared to vehicle or calcineurin inhibitor (tacrolimus)-treated cells. Sirolimus also reduced LDL uptake in iPSC-derived endothelial cells compared to vehicle or tacrolimus-treated cells. Tacrolimus was associated with a trend towards altered endothelial energetics. Tacrolimus and sirolimus exert differential endothelial cell functional profiles that do not fully explain the clinical outcomes observed suggesting a need to explore the drug endothelial profiles in the context of vascular injury and inflammation.
Abstract Tu058: Reverse Remodeling with LVAD Therapy is Associated with Alternative Splicing of CAMK2D
Authors: Thomas Martin, Dakota Hunt, Christopher Ebmeier, Amrut Ambardekar, peter buttrick, leslie leinwand
Journal: Circulation Research (2024)

Therapies for end-stage heart failure are lacking and the number of patients awaiting heart transplants far outweighs availability. Left ventricular assist devices (LVADs) take over cardiac pump function and are used as a bridge-to-transplant. Notably, some patients on LVADs experience recovery of cardiac function and reversal of pathological cardiac remodeling; however, the molecular mechanisms underlying these favorable outcomes are unknown. In this study, we studied 19 paired pre- and post-LVAD samples with 10 clinically categorized as responders and 9 as non-responders. Bulk mRNA sequencing identified 486 differentially expressed genes post-LVAD, including reduced pro-inflammatory gene expression and increased expression of genes involved in metal ion binding; however, just 23 total genes were differentially expressed between responders and non-responders. To determine whether LVAD differentially impacted the proteome in responders and non-responders, we next performed quantitative proteomics on post-LVAD samples. This analysis identified 154 differentially expressed proteins and revealed that factors involved in mRNA processing were higher expressed in LVAD responders. Re-analysis of our mRNA sequencing data for gene isoforms identified that alternative splicing of calcium and calmodulin-dependent protein kinase 2-delta ( CAMK2D ) was the most significantly impacted event with non-responders having increased inclusion of exon 14 (denoting the B isoform), which encodes a nuclear localization sequence. Notably, there was a strong negative correlation between exon 14 inclusion and ΔLVEF post-LVAD. We validated these findings using targeted exon-specific quantitative PCR, which confirmed that expression of CAMK2D B was higher both pre- and post-LVAD in non-responders, while responders had post-LVAD levels matching non-failing controls. We next investigated whether responders and non-responders differed at the phospho-proteome level via mass spectrometry and found three serines in CaMK2δ exon 14 were the only differentially abundant phosphosites and all increased in non-responders. Localization studies in vitro with adenoviruses expressing phospho-null or phospho-mimetic CaMK2D B constructs revealed that these phosphorylation events precluded nuclear localization. In conclusion, we identified differential alternative splicing and phosphorylation of CaMK2δ in LVAD responders, which may represent novel therapeutic targets for heart failure recovery.
Abstract Tu010: Matrix metallopeptidase 9 contributes to the beginning of plaque and is a potential biomarker for the early identification of atherosclerosis in asymptomatic patients with diabetes
Authors: liping Su, Bingli Liu, Szejie Loo, Yu Gao, Ester Khin, Xiaocen Kong, Rinkoo Dalan, Xiaofei Su, Kok-Onn Lee, Jianhua Ma, Lei Ye
Journal: Circulation Research (2024)

Aims: To determine the roles of matrix metallopeptidase-9 (MMP9) on human coronary artery smooth muscle cells (HCASMCs) in vitro , early beginning of atherosclerosis in vivo in diabetic mice, and patients with diabetes. Methods: Active hMMP9 ( act-hMMP9) was added to HCASMCs and markers of inflammation were measured. Act-hMMP9 (n=16) or placebo (n=15) was administered to d i abetic KK.Cg- A y /J (KK) mice. Carotid artery inflammation and atherosclerosis measurements were made at 2 and 10 weeks after treatment. An observational study of newly diagnosed drug naïve patients with type 2 diabetes mellitus (T2DM n=234) and healthy matched controls (n=41) was performed and patients had ultrasound of carotid arteries and some had coronary computed tomography angiogram for the assessment of atherosclerosis. Serum MMP9 was measured and its correlation with carotid artery or coronary artery plaques were determined. Results: Act-hMMP9 induced inflammatory response in HCASMCs in vitro , including increased gene and protein expressions of MCP-1, ICAM-1, VCAM-1, and enhanced macrophage adhesion. Exogenous act-hMMP9 increased inflammation and initiated atherosclerosis in KK mice at 2 and 10 weeks: increased vessel wall thickness, lipid accumulation, and Galectin-3+ macrophage infiltration into the carotid arteries. In newly diagnosed T2DM patients, serum MMP9 correlated with carotid artery plaque size with a possible threshold cutoff point. In addition, serum MMP9 correlated with number of mixed plaques and grade of lumen stenosis in coronary arteries of patients with drug naïve T2DM. Conclusions: MMP9 contributes to the initiation of atherosclerosis and may be a potential biomarker for the early identification of atherosclerosis in patients with diabetes
Abstract Tu042: Fatty Acid Dysregulation Drives Cardio-Hepatic Crosstalk in Heart Failure with Preserved Ejection Fraction (HFpEF)
Authors: Bellina Mushala, Michael Stoner, Brenda McMahon, Amber Vandevender, Steven Mullett, Stacy Gelhaus, Michael Jurczak, Iain Scott
Journal: Circulation Research (2024)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome that accounts for nearly half of all heart failure cases world-wide. The pathophysiological mechanisms underlying HFpEF include a variety of extracardiac abnormalities such as metabolic derangements, arterial hypertension, and microvascular endothelial dysfunction, that all drive left ventricular remodeling and dysfunction. The phenotypic diversity presented in HFpEF involves functional and structural changes in several organs including the liver. As a highly vascularized organ, the liver is highly sensitive to any hemodynamic changes in the heart and clinical studies have established the presence of liver injury in HFpEF patients. However, there is limited evidence of this relationship in preclinical mouse models, thereby hindering the exploration of the pathological mechanisms linking the two organs. Cardio-hepatic interactions are poorly understood yet play a critical role in the pathophysiology of HFpEF where aberrant metabolic signaling pathways such as insulin resistance, inflammation and oxidative stress significantly contribute to disease progression and further perpetuate a vicious cycle of cardio-hepatic deterioration. Hypothesis: With limited preclinical data in the field, we sought to elucidate the potential pathophysiological mechanisms driving cardio-hepatic crosstalk in HFpEF. Methods: We used a two-hit preclinical mouse model that recapitulates cardiometabolic HFpEF to characterize the coexistence of cardiac and hepatic dysfunction in HFpEF. Male mice were kept on the HFpEF model for 15 weeks and subjected to echocardiography, glucose tolerance tests, histopathology, and multi-omics analyses. Results: We report that markers of HFpEF severity such as diastolic dysfunction and left ventricular hypertrophy, significantly correlated with hepatic injury and dysfunction that exacerbated metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Impaired energy substrate utilization due to fatty acid dysregulation was a major mechanism underlying cardio-hepatic crosstalk in HFpEF. Conclusion: Our findings highlight fatty acid metabolism as a potential target to mitigate inter-organ dysfunction in HFpEF, representing a promising opportunity to create new treatment paradigms and drive positive outcomes in HFpEF.
Abstract Tu053: Activin Signaling Inhibition Enhances Cardiac Functional Recovery After Aortic Debanding
Authors: Anand Singh, James Sawalla Guseh, Chunyang Xiao, Keith Babbs, Jasbir Seehra, Haobo LI, Anthony Rosenzweig
Journal: Circulation Research (2024)

Background: Human aortic stenosis (AS) induces adverse cardiac remodeling and heart failure by pressure overload. Reducing pressure overload (e.g., Trans-catheter aortic valve replacement (TAVR) mitigates or reverses adverse remodeling but these benefits are limited in many TAVR patients. Here we established a murine transverse-aortic-constriction (TAC)-debanding model to mimic TAVR and identify ways to enhance reverse remodeling. Methods: 10-week-old wild-type C57BL/6 mice were subjected to TAC surgery and debanding by suture removal, or sham-debanding, between 4 (short duration) and 10 weeks (long duration) after TAC. Echocardiography was performed to assess cardiac function. RNA sequencing (RNAseq) of TAC and debanded hearts demonstrated activation of activin signaling with TAC that was relieved by debanding. Based on this, TAC-debanded animals were treated with an investigational modified activin receptor type IIB ligand trap, RKER-012 (10 mg/kg IP, bi-weekly), to inhibit signaling downstream of activin and related ligands. Results: Serial echocardiography of TAC-debanded animals showed greater dysfunction with longer duration TAC (Fractional shortening [FS]=39.2±3.84 for 4 weeks-TAC vs Sham: 61.2±0.94, p&lt;0.05; FS=18.2±1.80 for 10 weeks-TAC vs Sham-TAC: 64.7±0.43, p&lt;0.05). Cardiac functional recovery was slower and less complete in animals with longer duration TAC (10 weeks after debanding with TAC for 4 weeks, FS=57.8±1.41 vs 46.6±3.4 TAC for 10 weeks). RNAseq analysis of hearts post-debanding (10 weeks TAC+10 weeks debanding) showed a 5.73-fold decrease (p=2.57x10 -16 ) in FSTL3 expression, a biomarker of activin pathway signaling, suggesting a decrease in activin signaling accompanied functional recovery. To assess functional contribution of activin signaling to incomplete recovery and therapeutic potential of pathway inhibitors, we treated debanded animals (debanded 8 weeks post-TAC) with RKER-012 or placebo (TBS) for 4 weeks. RKER-012-treated mice showed significantly increased ejection fraction (54.12±1.50 vs placebo control 42.88±3.21; p=0.001) and reduced heart weight (p=0.01). Conclusions: Debanding after TAC mitigates adverse remodeling that is slower and less complete with longer duration TAC. A ligand trap (RKER-012) that was designed to inhibit signaling downstream of activin enhanced recovery after debanding and warrants further study as a potential therapeutic intervention in patients with incomplete functional recovery after TAVR.
Abstract Tu050: Deficiency Of Mitochondrial Disulfide Relay Carrier Leads To Cardiac Hypertrophy
Authors: Alexander Karius, Jin Ma, Annie Son, Abu Syed, Pingyuan Wang, Paul Hwang
Journal: Circulation Research (2024)

Background: Innate immune activation is critical for cardiac hypertrophy; however, its upstream regulation is less well understood. Coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4) is an essential carrier for the import of various mitochondrial proteins including TP53 -regulated inhibitor of apoptosis 1 (TRIAP1). CHCHD4 was recently identified as a dysregulated gene in patients with dilated cardiomyopathy and was separately found to mediate innate immune signaling in skeletal muscle. Therefore, we hypothesized that CHCHD4 may play a role in the development of cardiac hypertrophy by regulating innate immunity. Methods: Genetically modified C57BL/6 mice overexpressing CHCHD4 (CHCHD4 Tg) or haploinsufficient in CHCHD4 ( CHCHD4 +/- ) were utilized. Mice were injected either with low dose (2 mg/kg) or high dose (30 mg/kg) isoproterenol (ISO) daily for up to 3 wk to induce hypertrophy. Results: CHCHD4 +/- mice developed cardiac hypertrophy (HW/BW (mg/g): 3.62 ± 0.15 CHCHD4 +/- vs 2.70 ± 0.13 wild-type (WT) or 2.55 ± 0.16 CHCHD4 Tg, p&lt;0.0001) when allowed to age to 28 wk and showed reduced left ventricular ejection fraction (EF) at 1 year when compared with wild-type or CHCHD4 Tg mice (EF (%): 50.94 ± 0.94 CHCHD4 +/- vs 58.33 ± 0.78 wild-type or 57.88 ± 1.32 CHCHD4 Tg, p&lt;0.0001). After low dose ISO treatment, CHCHD4 +/- mice had reduced EF at 2 wk compared to WT or CHCHD4 Tg mice (EF (%): 44.60 ± 1.74 CHCHD4 +/- vs 54.28 ± 0.86 wild-type, p&lt;0.0001; or vs 52.76 ± 1.33 CHCHD4 Tg, p=0.0006). After high dose ISO treatment, WT mice developed cardiac hypertrophy by 1 wk and impaired EF by 3 wk, while CHCHD4 Tg mice remained normal. ISO treatment caused reduction of CHCHD4 levels in both the 24 hr and 1 wk states. This reduction was associated with decreased TRIAP1 and activation of the cGAS-STING-NFkB pathway in wild-type, but not CHCHD4 Tg mice. Further, plasma mitochondrial DNA (mtDNA) was 2.3 times higher in WT mice treated with high dose ISO for 1 wk compared to WT control (n=8-11/group, p=0.011), while that of CHCHD4 Tg mice was not significantly changed by ISO treatment. Conclusions: Our findings suggest that CHCHD4 may be a key upstream regulator of innate immune activation mediating cardiac hypertrophy and that cell-free mtDNA in blood could be a potential biomarker of pathogenesis.
Abstract Tu036: Adipose tissue plasticity in response to early pathological stress on the heart and mediation by adipose thermogenic activation
Authors: Natasha Maria James, Azariyas Challa, Pablo Vidal Souza, Parth Pardeshi, Santosh Maurya, Yang Wang, Lisa Baer, Andrew Carley, E Douglas Lewandowski, Kristin Stanford
Journal: Circulation Research (2024)

Background: Cardiovascular diseases (CVD) are the leading cause of death globally, accounting for approximately 17.9 million mortalities per year. Previous studies have shown that there is an early response of white and brown adipose tissue (WAT and BAT, respectively) to pathological stress on the heart prior to cardiac dysfunction. Interestingly, human subjects with detectable BAT activity (a thermogenic tissue) exhibit a reduced risk of Congestive Heart Failure, but the mechanism for this is unclear. We hypothesized that increasing the thermogenic acitivity of adipose tissue would be beneficial during the initial cardiac hypertrophic signaling prior to the development of compensatory hypertrophy. Methods: We studied both WAT and BAT in male and female C57BL/6J mice subjected to cardiac pressure overload via transaortic constriction (TAC). 24 hours post-surgery, mice were subjected to room temperature (RT) 22° C or mild cold 16°C to stimulate BAT activation for 48 hours after which tissues were collected. The study groups included: SHAM RT, TAC RT, SHAM COLD, TAC COLD. We used uncoupling protein 1 knockout (UCP1-KO) mice, with impaired thermogenic activity as a negative control. Results: At 72 hours post tac surgery, expression of thermogenic and metabolic genes remained unchanged in BAT and WAT of both sexes. However, mild cold exposure resulted in an increase in UCP1 expression in BAT of male, but not female mice while other metabolic and thermogenic gene markers’ expression was increased in a sex-specific manner. Adaptations to scWAT were more moderate than BAT, with an increase in Ucp1 after cold exposure in both sexes. Moreover, 48 hours of cold exposure attenuated expression of gene markers for hypertrophic signaling in the heart during TAC. Importantly, these adaptations were absent in UCP1-KO mice, signifying that intact thermogenic activity in adipose tissue was required for the attenuated expression of hypertrophic markers in the heart. Interestingly, cardiac fibrosis markers were downregulated with TAC-Cold in male mice only, suggesting a stronger response compared to female mice. Conclusions: Our findings demonstrate that pathological stress on the heart during TAC does not impact adipose tisse thermogenesis. Additionally, activating thermogenic gene expression of adipose tissue via cold exposure mediates the early induction of hypertrophic signaling in the heart within 72 hours of TAC. Notably, adipose tissue plasticity is sex-specific.
Abstract Tu149: FDA-Approved Antidepressant Trazodone Potentially Increases the Risk of Dyslipidemia
Authors: Naara Ramirez, Yipeng Sui
Journal: Circulation Research (2024)

Cardiovascular disease is the leading cause of death. Many cardiovascular health problems, such as atherosclerosis, are caused by dyslipidemia. One xenobiotic nuclear receptor, Pregnane X Receptor (PXR), plays a significant role in atherosclerosis and dyslipidemia, and is activated by various environmental chemicals, including endocrine-disrupting chemicals (EDCs). EDCs are found in common household items such as plastics, medications, and food. Trazodone is a clinically used medication to treat depression by aiding in restoring the balance of serotonin in the brain. But it is unclear if Trazodone has possible impacts on cardiovascular risk factors such as dyslipidemia. Our preliminary data suggested that Trazodone activated human PXR in both intestinal (LS180) and hepatic (HepG2) cells. We hypothesize that Trazodone could regulate the cholesterol uptake mediated by PXR signaling. In this study we use cell-based transfection assay to evaluate the underlying mechanisms by which Trazodone activates PXR. We found that Trazodone was a more potent agonist of human PXR than mouse PXR. Trazodone could activate PXR more intensely in human liver cells compared with human intestinal cells. Our data suggested that Trazodone was a selective PXR agonist and promoted the dissociation between PXR and its nuclear corepressors. Next, we are to identify the key amino acid residues within PXR ligand binding pocket that interact with Trazodone by using computational docking study along with site-mutagenesis assay. Furthermore, we plan to estimate if Trazodone altered cholesterol uptake by human intestinal cells using fluorescence-labeled cholesterol. In conclusion, we explore the potential molecular mechanisms of how FDA-approved antidepressant Trazodone activates human PXR and increases the possible risk of dyslipidemia, which provides potential evidence on future cardiovascular disease risk assessment for Trazodone as well as other antidepressant drugs.