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Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy

Reiss, Allison B; Arain, Hirra A; Kasselman, Lora J; Renna, Heather A; Zhen, Juan; Voloshyna, Iryna; DeLeon, Joshua; Carsons, Steven E; Petri, Michelle
Background andObjectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.
PMID: 31438615
ISSN: 1648-9144
CID: 4054012

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs

Barberio, Matthew D; Kasselman, Lora J; Playford, Martin P; Epstein, Samuel B; Renna, Heather A; Goldberg, Madeleine; DeLeon, Joshua; Voloshyna, Iryna; Barlev, Ashley; Salama, Michael; Ferrante, Sarah C; Nadler, Evan P; Mehta, Nehal; Reiss, Allison B; Freishtat, Robert J
BACKGROUND:Macrophage cholesterol efflux capacity has been identified as a predictor for cardiovascular disease. We assessed the relationship between adipocyte-derived extracellular vesicle microRNAs and macrophage cholesterol efflux capacity. METHODS:) for: (1) cholesterol efflux capacity and lipoprotein profiles; (2) adipocyte-derived extracellular vesicle microRNAs in serum; (3) the role of visceral adipose tissue extracellular vesicle in regulation of cholesterol efflux and cholesterol efflux gene expression in THP-1 macrophages in vitro. RESULTS:Efflux capacity was significantly associated with HDL (r = 0.30, p = 0.01) and LDL (r = 0.33, p = 0.005) particle size. Multivariate-analysis identified six microRNAs associated (p < 0.05) with cholesterol efflux capacity: miR-3129-5p (Beta = 0.695), miR-20b (0.430), miR9-5p (0.111), miR-320d (- 0.190), miR301a-5p (0.042), miR-155-5p (0.004). In response to increasing concentrations (1 μg/mL vs. 3 μg/mL) of VAT extracellular vesicle, cholesterol efflux (66% ± 10% vs. 49% ± 2%; p < 0.01) and expression of ABCA1 (FC = 1.9 ± 0.8 vs 0.5 ± 0.2; p < 0.001), CD36 (0.7 ± 0.4 vs. 2.1 ± 0.8, p = 0.02), CYP27A1 (1.4 ± 0.4 vs. 0.9 ± 0.5; p < 0.05), and LXRA (1.8 ± 1.1 vs. 0.5 ± 0.2; p < 0.05) was altered in THP-1 cells in vitro. CONCLUSION/CONCLUSIONS:Adipocyte-derived extracellular vesicle microRNAs may, in part, be involved macrophage cholesterol efflux regulation.
PMCID:6647309
PMID: 31331347
ISSN: 1479-5876
CID: 4014902

ATHEROPROTECTIVE ACTIONS OF OXYTOCIN IN HUMAN MACROPHAGES: REDUCED LIPID ACCUMULATION UNDER INFLAMMATORY CONDITIONS

Karten, Ariel; Kasselman, Lora; Renna, Heather A; Lam, Eric; Glass, Daniel S; Vernice, Nicholas A; DeLeon, Joshua; Reiss, Allison
CINAHL:135346080
ISSN: 0735-1097
CID: 3818992

Is intra-procedure three-dimensional transesophageal echocardiogram an alternative to preprocedure multidetector computed tomography for the measurement of the aortic annulus in patients undergoing transcatheter aortic valve replacement?

Hafiz, Abdul Moiz; Medranda, Giorgio A; Kakouros, Nikolaos; Patel, Jay; Kahan, Jonathan; Gubernikoff, George; Ray, Beevash; Paruchuri, Vijayapraveena; DeLeon, Joshua; Marzo, Kevin; Calixte, Rose; Gaztanaga, Juan
BACKGROUND:The role of three-dimensional transesophageal echocardiography (3DTEE) vs multidetector computed tomography (MDCT) in aortic annular sizing has been poorly defined in patients undergoing transcatheter aortic valve replacements (TAVR). We set to determine the correlation between 3DTEE and MDCT in measuring the aortic annulus prior to TAVR. METHODS:In an observational, retrospective study, we compared aortic annular areas measured by MDCT and 3DTEE in TAVR patients. The aortic annular area was measured by planimetry of images obtained by MDCT pre-TAVR and by intra-TAVR TEE using 3D rendering of the aortic annulus followed by planimetry. Our primary outcome was degree of correlation between mean aortic annulus area by 3DTEE and MDCT. RESULTS:. There was a strong positive linear correlation between aortic annular area measurements obtained from these two modalities with mild relative underestimation by 3DTEE (ρ=.833). This relationship can be estimated using the predictive formula: [Formula: see text] CONCLUSIONS: Three-dimensional transesophageal echocardiography measurements have a high degree of correlation with MDCT measurements and thus can assist in proper valve prosthesis selection for TAVR. Our study thus supports use of 3DTEE as a reasonable alternative imaging modality in patients undergoing TAVR.
PMID: 28722306
ISSN: 1540-8175
CID: 3406942

PRO-ATHEROGENIC PROPERTIES OF PLASMA FROM PATIENTS WITH TYPE 1 DIABETES MELLITUS: EFFECTS ON MACROPHAGE LIPID HANDLING [Meeting Abstract]

DeLeon, Joshua R; Corletto, Jorge Mejia; Accacha, Siham; Voloshyna, Iryna; Siegart, Nicolle; Kasselman, Lora; Magana, Mariano Castro; Reiss, Allison
ISI:000397342302789
ISSN: 1558-3597
CID: 2677992

Impact of first contact on symptom onset-to-door time in patients presenting for primary percutaneous coronary intervention

Hafiz, Abdul Moiz; Naidu, Srihari S; DeLeon, Joshua; Islam, Shahidul; Alkhatib, Basil; Lorenz, Miguel; D'Elia, Alexis; Rosenthal, Barry; Marzo, Kevin
OBJECTIVES/OBJECTIVE:To determine effect of first medical contact type on symptom onset-to-door time (SODT). BACKGROUND:Shorter total ischemic time is associated with improved outcomes in ST-elevation myocardial infarction. METHODS:From 2005 to 2009, we reviewed records of all consecutive patients treated with primary percutaneous coronary intervention for ST-elevation myocardial infarction at our tertiary care teaching hospital (median follow-up 3.85 years). We compared SODT in patients whose first medical contact was a private physician (in person or via telephone) vs patients who presented to the emergency department (ED) directly (in person or via Emergency Medical Services). RESULTS:Of 366 patients, 84 (23%) contacted a physician (group A) while 282 (77.6%) did not (group B). Group A had higher median SODT (239.5 vs 130 minutes, P = .0043) and significantly higher mortality (log rank P = .0392, Cox Proportional Hazard Model risk factors: physician contact first [P < .013], age [P < .0001] and peripheral vascular disease [P < .035]). Two factors associated with prolonged SODT: (1) contacting a physician first P = .002 and (2) personal mode of transportation, P = .002. Patients presenting during "on-hours" (weekdays) were more likely to first contact a physician compared with those presenting during "off-hours" (weeknights and weekends) (66.67% in group A vs 45.04% in group B, P < .001). CONCLUSIONS:Patients whose first medical contact was a physician had greater pre-hospital delays and worse survival compared to those who sought emergent medical care directly. This pattern occurred more often during "on-hours." Educational efforts aimed at both patient and physician office practices are warranted.
PMID: 23623235
ISSN: 1532-8171
CID: 3406932

IMMEDIATE AND EARLY EFFECTS OF ALCOHOL SEPTAL ABLATION ON THE RIGHT HEART AND LEFT ATRIUM [Meeting Abstract]

Ray, Beevash; Lachmann, Justine; Cohen, Jerald L.; Gubernikoff, George; DeLeon, Joshua R.; Gaztanaga, Juan; Michelakis, Nickolaos; Naidu, Srihari S.
ISI:000302326700243
ISSN: 0735-1097
CID: 3406922

Circulating endothelial microparticles in diabetes mellitus

Tramontano, A F; Lyubarova, R; Tsiakos, J; Palaia, T; Deleon, J R; Ragolia, L
BACKGROUND:Endothelial Microparticles (EMPs) are small vesicles shed from activated or apoptotic endothelial cells and involved in cellular cross-talk. Whether EMP immunophenotypes vary according to stimulus in Diabetes Mellitus (DM) is not known. We studied the cellular adhesion molecule (CAM) profile of circulating EMPs in patients with and without Diabetes Mellitus type 2, who were undergoing elective cardiac catheterization. METHODS AND RESULTS/RESULTS:EMPs were analyzed by flow cytometry. The absolute median number of EMPs (EMPs/microL) specific for CD31, CD105, and CD106 was significantly increased in the DM population. The ratio of CD62E/CD31 EMP populations reflected an apoptotic process. CONCLUSION/CONCLUSIONS:Circulating CD31+, CD105+, and CD106+ EMPs were significantly elevated in patients with DM. EMPs were the only independent predictors of DM in our study cohort. In addition, the EMP immunophenotype reflected an apoptotic process. Circulating EMPs may provide new options for risk assessment.
PMCID:2904448
PMID: 20634911
ISSN: 1466-1861
CID: 4954992

Prostaglandin D2 synthase isoforms and diabetic vasculopathy [Meeting Abstract]

Tramontano, Anthony F.; Hall, Christopher; Kodali, Visali; DeLeon, Joshua R.; Ragolia, Louis
ISI:000253997102127
ISSN: 0735-1097
CID: 3406912

Adherence to the American college oi cardiology/American society of nuclear cardiology appropriateness criteria for single-photon emission computed tomography myocardial perfusion imaging [Meeting Abstract]

Kerwin, Todd C.; Lo, Ronald; D'Anca, Michael; DeLeon, Joshua R.
ISI:000244651801072
ISSN: 0735-1097
CID: 3388342