Late-Breaking Basic Science Abstracts From the American Heart Association’s Scientific Sessions 2021
2021; Lippincott Williams & Wilkins; Volume: 129; Issue: 12 Linguagem: Inglês
10.1161/res.0000000000000520
ISSN1524-4571
AutoresOlivia T Ly, Grace E. Brown, Hanna Chen, Liang Hong, Xinge Wang, Yong Duk Han, Mahmud Arif Pavel, Arvind Sridhar, Mark Maienschein‐Cline, Sang Ging Ong, Khaled Abdelhady, Malek G. Massad, Lona Ernst Rizkallah, Jalees Rehman, Salman R. Khetani, Dawood Darbar, Univ of Illinois COM, Chicago, Chicago, Univ of Illinois at Chicago, Orland Park, Chicago, Univ of Illinois at Chicago, Chicago, Univ of Illinois, Chicago, Chicago, Univ of Illinois Chicago, Chicago, Il,
Tópico(s)Health and Medical Research Impacts
ResumoHomeCirculation ResearchVol. 129, No. 12Late-Breaking Basic Science Abstracts From the American Heart Association's Scientific Sessions 2021 Free AccessAbstractPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAbstractPDF/EPUBLate-Breaking Basic Science Abstracts From the American Heart Association's Scientific Sessions 2021 Originally published2 Dec 2021https://doi.org/10.1161/RES.0000000000000520Circulation Research. 2021;129:e234–e246Late-Breaking Basic Science: Mechanisms of Cardiac Development and Disease16222: Combinatorial Maturation of Patient Stem Cell-Derived Atrial Cardiomyocytes Unmasks Mechanism of Atrial Fibrillation Induced by NPPA Gene MutationOlivia T Ly1, Grace Brown2, Hanna Chen3, Liang HONG4, Xinge Wang, Yong Duk Han4, Mahmud Arif Pavel1, Arvind Sridhar5, Mark Maienschein-Cline3, Sang Ging Ong1, khaled Abdelhady, Malek G Massad6, Lona Ernst Rizkallah1, Jalees Rehman4, SALMAN KHETANI, Dawood Darbar4; 1Univ of Illinois COM, Chicago, Chicago, IL, 2Univ of Illinois at Chicago, Orland Park, IL, 3Chicago, IL, 4Univ of Illinois at Chicago, Chicago, IL, 5Univ of Illinois, Chicago, Chicago, IL, 6Univ of Illinois Chicago, Chicago, IL,Introduction: Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) are ideally suited for modeling heritable atrial fibrillation (AF) and testing personalized pharmacological therapy, but there is limited data on the maturation of iPSC-atrial (a) CMs. While we reported the only non-ion channel gene (NPPA), encoding atrial natriuretic peptide (ANP), as a cause of familial AF, the underlying cellular mechanisms remain unclear. Immaturity of iPSC-aCMs is one potential explanation. Hypothesis: We hypothesized that a combinatorial engineering approach to maturation with biochemical cues (T3 [T], IGF-1[I], dexamethasone [D]; [TID]), bioenergetic supplement (fatty acids [FA]), and electrical stimulation (ES), synergistically promotes the electrophysiological (EP), structural, and metabolic maturity of iPSC-aCMs to a level comparable to human atrial tissue (HAT) and will unmask the underlying cellular mechanisms of an NPPA mutation. Methods: We differentiated iPSC-aCMs with retinoic acid, applied TID+FA+ES, and compared the EP (patch clamping, optical voltage mapping), structural (immunofluorescence, western blots [WB]), metabolic (Seahorse Analyzer, WB, RT-PCR), and transcriptomic (RNA-seq) maturity with immature iPSC-aCMs and adult human aCMs from the same patient. We generated iPSC-aCMs from a family carrying the NPPA-S64R mutation, an isogenic control using CRISPR-Cas9, and used our matured iPSC-aCMs to elucidate the EP signature of AF. Results: TID+FA+ES treated iPSC-aCMs displayed improved sarcomeric organization and oxidative capacity (Figure 1a,b), more hyperpolarized RMP and increased APA (Figure 1c,d). Only mature NPPA-S64R iPSC-aCMs prolonged APD, and increased IKs density when compared to immature aCMs (Figure 1e,f,g,h). Conclusion: We established a combinatorial engineering approach that promoted the comprehensive maturation of iPSC-aCMs and unmasked the underlying mechanism of an AF-causing NPPA mutation.Download figureDownload PowerPointAuthor Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Atrial fibrillation; Cellular Electrophysiology; Stem cell biology; Gene mutations; Cellular Engineering16143: The Pathogenesis of Covid-19 Myocardial Injury: An Immunohistochemical Study of Postmortem BiopsiesCamila Hartmann1, Anna Flavia Ribeiro dos Santos Miggiolaro1, Jarbas da Silva Motta Junior2, Lucas Baena Carstens3, Caroline Busatta Vaz De Paula3, Sarah Fagundes Grobe1, Larissa Hermann de Souza Nunes2, Gustavo Lenci Marques1, Peter Libby4, Lídia Zytynski Moura1, Lucia de Noronha3, Cristina Pellegrino Baena1; 1PUCPR; Marcelino Champagnat Hosp, Curitiba, Brazil, 2Marcelino Champagnat Hosp, Curitiba, Brazil, 3PUCPR, Curitiba, Brazil, 4Brigham and Womens Hosp, Cambridge, MAIntroduction: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. Hypothesis: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. Methods: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1β, IL-4, IL-6, CD163, TNF-α, TGF-β, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Results: Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1β, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. Conclusions: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-β and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.Download figureDownload PowerPointAuthor Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Myocardium; COVID-19; Endothelium; Fibrosis; Pathology16724: Mitochondrial Optogenetic-Mediated Preconditioning Protects Cardiomyocytes From Stress-Induced InjurySeulhee Kim1, Patrick Ernst2, Yingnan Si1, Taehyun Kim1, Min Xie1, Margaret Liu2, Lufang Zhou1; 1Univ of Alabama Birmingham, Birmingham, AL, 2Univ of Alabama at Birmingham, Birmingham, AL,Background: While mounting evidence indicates that mitochondria, the cell powerhouse, is involved preconditioning-mediated cytoprotection, the role of mitochondrial membrane potential (ΔΨm) in this process is not well defined. Recently, our lab developed a novel mitochondrial-targeted optogenetic technology (mOpto) that can induce light intensity-dependent dynamic ΔΨm depolarization in a variety of cell types. The aim of this study was to utilize mOpto to examine the role of ΔΨm preconditioning in protecting cells against stress-induced injury. Methods: Cardiomyocytes expressing mOpto gene were subjected to transient, low intensity LED illumination (3 hours, 0.2 mW/mm2), followed by exposing to various stress such as FCCP (20 μM, 24 hours), H2O2 (200 μM, 24 hours), or ischemia-reperfusion (I2/R4: glucose-free medium and 0% O2 for 2 hours, and complete culture medium and oxygenated for 4 hours). Cell viability, ΔΨm and reactive oxygen species (ROS) were measured before and after stress. Results: Our data showed that cell viability is significantly higher in preconditioned cells compared to the control groups post I2/R4 treatment, along with reduced ROS level and alleviated ΔΨm depolarization (see figure). The mOpto-mediated preconditioning also protected cells from FCCP and H2O2 treatments to different extents. Analysis performed immediately after preconditioning indicated a slight ROS increase and ΔΨm dissipation, compared to controls. Moreover, Parkin-deficiency attenuated mOpto preconditioning-mediated cytoprotection, suggesting involvement of Parkin-dependent signaling cascades such as mitophagy. Conclusion: mOpto-medicated ΔΨm preconditioning effectively protected cardiomyocytes from cell injury induced by various stress, likely through Parkin-dependent mitophagy. Future studies will determine whether this process is ROS-dependent.Download figureDownload PowerPointThis research has received full or partial funding support from the American Heart Association.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Mitochondria; Preconditioning; Cell physiology17158: Cardiomyocyte Specific Deletion Of Trpv4 Offers Cardio-protection Independent Of Cardiac Fibrosis Following Pressure Overload-induced HypertrophyRavi K Adapala1, Venkatesh Katari1, Vahagn A Ohanyan2, William M Chilian3, Sailaja M Paruchuri4, Charles Thodeti1; 1Univ of Toledo, Toledo, OH, 2Northeast Ohio Med Univ, Rootstown, OH, 3NORTHEAST OHIO MEDICAL UNIV, Rootstown, OH, 4UNIVERSITY OF TOLEDO, TOLEDO, OH,Prolonged changes in hemodynamic pressure due to pathological insults disrupts the electrical and biomechanical coupling between cardiomyocytes which leads to heart failure. However, the mechanotransduction pathways that regulate cardiomyocyte hypertrophy in response to pathological stress are still unknown. Transient receptor potential vanilloid 4 ion channel (TRPV4) is a mechanosensitive ion channel implicated in cardiac fibrosis and cardiomyocyte dysfunction. We have recently shown that global deletion of TRPV4 preserves cardiac function and structure via reducing cardiac fibrosis after MI. Here, we investigated cardiomyocyte specific role of TRPV4 following pressure overload (transverse aortic constriction; TAC) induced hypertrophy. TRPV4 expression was increased in the hearts of wild type (WT) mice following TAC with concomitant increase in myocyte cross-sectional area, cardiac fibrosis and reduced ejection fraction. However, myocardial structure and function was preserved in global TRPV4KO mice compared to WT, 28 days after TAC. To investigate cardiomyocyte specific role of TRPV4, we have generated cardiomyocyte specific TRPV4 knockout mice (TRPV4CMKO) by crossing TRPV4lox/lox with Myh6cre mice. First, TRPV4 deletion in cardiomyocytes was confirmed through genotyping and real time PCR in tail snips and isolated cardiomyocytes. Next, we subjected the TRPV4lox/lox and TRPV4CMKO to TAC and then measured cardiac function. We found that cardiac hypertrophy (cardiomyocyte cross sectional area) and cardiac fibrosis was increased in both TRPV4lox/lox and TRPV4CMKO mice compared to respective sham controls. In contrast, absence of TRPV4 in cardiomyocytes preserved the cardiac function compared to TRPV4lox/lox mice. Further RNA sequencing analysis revealed that TAC upregulated hypertrophic genes in TRPV4lox/lox hearts but downregulated in TRPV4CMKO hearts. Our results indicate that cardiomyocyte specific deletion of TRPV4 alone preserves cardiac function despite of increased remodeling of the heart by downregulating hypertrophic genes and identify TRPV4 as new cardiomyocyte therapeutic target for the heart failure.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Calcium; Cardioprotection; Cardiac hypertrophy; Fibrosis16845: The Aldose Reductase Inhibitor At-001 Improves Cardiac Efficiency and Decreases Diastolic Dysfunction in an Animal Model of Diabetic Cardiomyopathy: Comparative and Add-On Studies versus SGLT-2 InhibitionQutuba Karwi1, Keshav Gopal1, Seyed Amirhossein Tabatabaei Dakhili1, Cory S Wagg2, Riccardo Perfetti3, Ravichandran Ramasamy4, John R Ussher1, Gary D Lopaschuk1; 1Univ of Alberta, Edmonton, Canada, 2Univ of Alberta, Edmonton Ab, Canada, 3Applied Therapeutics, New York, NY, 4NYU Grossman Med Cntr, New York, NY,Introduction: Diabetic cardiomyopathy (DbCM) increases mortality and morbidity in type 2 diabetes (T2D) subjects. Increased aldose reductase (AR) activity has been linked to the impairment of cardiac energy metabolism and function in DbCM subjects. AR inhibition has been shown to be cardioprotective in DbCM mice. Dapagliflozin, a sodium-glucose cotransporter inhibitor, reduces the risk of cardiovascular death independent of diabetes status. Hypothesis: Concomitant administration of the AR inhibitor (AT-001) with dapagliflozin improves cardiac function and decreases diastolic dysfunction in DbCM. Methods: DbCM was established in human AR overexpressing transgenic (hAR-Tg) mice by subjecting them to a high-fat diet (60% kcal from lard) for 10-wk with a single intraperitoneal streptozotocin injection (75 mg/kg) at 4-wk. Male mice (n=4-6/group) were randomized to receive either vehicle, AT-001 (40 mg/kg/day), dapagliflozin (1 mg/kg/day), or a combination of AT-001plus dapagliflozin for 3-wk. Results: AT-001 treatment decreased cardiac fatty acid oxidation in DbCM mice, an effect that was associated with a reduction in pathological cardiac remodelling as indicated by a change in left ventricular mass. Cardiac efficiency (cardiac work/TCA activity) was also improved by AT-001 treatment. These benefits were unique to the treatment with AT-001. When potential synergistic effects were examined, cardiac function was significantly improved in the AT001+dapagliflozin-treated DbCM mice, as reflected by an improved diastolic function in vivo (a decrease in the E/e' ratio) and an increase in cardiac work in isolated working hearts (2.4 ± 0.04 vs 1.9 ± 0.03 joules/min/g dry wt) compared to the dapagliflozin-treated DbCM mice, p<0.05). This cardioprotection did not involve changes in myocardial oxygen consumption in the DbCM mice and treatment with AT001+dapagliflozin significantly enhanced cardiac efficiency (cardiac work/O2 consumption) in the DbCM mice (61.54 ± 0.7 vs 52.63 ± 2.0 μmol/min/g dry wt in the dapagliflozin-treated DbCM mice, p<0.05). Conclusion: AT-001 provides a unique profile in halting the progression of DbCM. AT-001 both alone and in combination with SGLT-2 inhibition may be beneficial in targeting the pathogenesis of DbCM.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Cardiac metabolism; Cardiomyopathy; Diabetes (Type II); Sodium glucose co-transporter 2 inhibitorsLate-Breaking Basic Science: Emerging Mechanisms and Therapies for Vascular Disease16648: Sacubitril-Valsartan Protects Against Aortic Aneurysm Progression via Regulating Neprilysin-Induced Vascular Smooth Muscle Cell ApoptosisSeung-Jun Lee1, Subin Jung1, Tae Wook Noh1, Hyo-Hyun Kim1, Jung-Hwan Kim1, Hyun-Chel Joo1, Chul-min Ahn2, Young-Guk Ko3, Donghoon Choi4; 1Severance Cardiovascular Hosp, Seoul, Korea, Republic of, 2Yonsei Univ Health System, Seoul, Korea, Republic of, 3Yonsei Cardiovascular Cntr, Seoul, 4Severance Hosp, Seoul, Korea, Republic ofBackground: Sacubitril/Valsartan (Sac/Val), an angiotensin II (Ang II) receptor-neprilysin inhibitor, is a potent drug for heart failure. However, its potential benefit in other cardiovascular disease is not understood. We sought to investigate the pathogenetic role of neprilysin in abdominal aortic aneurysm (AAA), and therapeutic effect of Sac/Val for amelioration of AAA progression. Methods and Results: Expression of neprilysin was investigated using human AAA tissue undergoing graft replacement and normal human aorta acquired during heart transplantation. Immunoblotting (Figure 1A) and immunofluorescence staining demonstrated a strong expression of neprilysin in AAA tissues, particularly in the vascular smooth muscle cell (VSMC). Sixteen weeks old ApoE-/- male mice fed an atherogenic diet were administered with vehicle, Val (26 mg/kg/day), or Sac/Val (31 mg/kg/day of Sac, 26 mg/kg/day of Val) for 28 days with Ang II infusion (1000 ng/kg/min). Assessment for the progression of AAA via in vivo magnetic resonance imaging and ex vivo histological analysis (Figure 1B) revealed that the maximal diameter of AAA was markedly suppressed by Sac/Val treatment compared with Val (0.87±0.05 vs. 1.28±0.16 mm, p=0.018, n=8 for each group), or vehicle (0.87±0.05 vs. 1.52±0.16 mm, p<0.001, n=8). Mechanistically, neprilysin upregulation in human aorta promoted the apoptosis of VSMC (Figure 1C), an integral component of vascular integrity, via PDGF-B dependent mechanism. Gene-set enrichment analysis also demonstrated upregulation of genes related to apoptosis of VSMC in the human VSMC transfected with neprilysin. Conclusion: We demonstrate a distinct expression of neprilysin in human AAA tissue, and the pharmacological inhibition of neprilysin substantially alleviated the progression of AAA in murine AAA model, thus paving a way for future application of Sac/Val for treatment of AAA to avoid high-risk vascular surgery.Download figureDownload PowerPointAuthor Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Abdominal aortic aneurysm; Vascular medicine16606: Oxidative Stress-Induced Endothelial Dysfunction and Decreased Vascular Nitric Oxide in Covid-19 PatientsVirginie Montiel1, Irina Lobysheva2, Ludovic Gérard3, Marjorie Vermeersch4, David Perez-Morga4, Thomas Castelein3, Jean Baptiste Mesland3, Philippe Hantson3, Christine Collienne3, Damien Gruson3, Marie-Astrid van Dievoet3, Alexandre Persu5, Christophe Beauloye6, Mélanie Dechamps7, Leïla Belkhir3, Annie Robert8, Marc Derive9, Pierre-François Laterre3, A.H.J Danser10, Xavier Wittebole3, Jean-Luc Balligand1; 1FATH - IREC / Cliniques Universitaires Saint Luc, Brussels, Belgium, 2FATH - IREC, Brussels, Belgium, 3Cliniques Universitaires Saint Luc, Brussels, Belgium, 4ULB, Gosselies, Belgium, 5Cliniques Universitaires Saint-Luc, Brussels, Belgium, 6IREC - UCL, Brussels, Belgium, 7CARD - IREC / Cliniques Universitaires Saint Luc, Brussels, Belgium, 8EPID - IREC, Brussels, Belgium, 9Inotrem SA, Vandoeuvre-les-Nancy, France, 10Erasmus MC, Rotterdam, NetherlandsIntroduction: SARS-CoV-2 targets endothelial cells through the angiotensin-converting enzyme 2 receptor. Hypothesis: The impact of the resulting endothelial injury is currently unknown but may contribute to the pro-coagulant state classically described during Covid-19. Methods: We prospectively compared clinical and biological parameters in 30 ICU- and 30 non-ICU-admitted Covid-19 patients, 10 ICU-admitted patients with septic shock unrelated to Covid-19 and 15 matched control subjects for similar cardiovascular risk factors as ICU Covid-19. Main Results: Early SARS-CoV-2 infection was associated with an imbalance between an exacerbated oxidative stress (plasma peroxides levels in ICU patients vs. controls: 1456.0 ± 400.2 vs 436 ± 272.1 mmol/L; P< 0.05) and a reduced nitric oxide bioavailability (nitrosylated hemoglobin, HbNO) proportional to disease severity (HbNO in ICU patients vs. controls: 116.1 ± 62.1 vs. 163.3 ± 46.7 nmol/L; P< 0.05). HbNO levels inversely correlated with oxygenation parameters in Covid-19 patients. Plasma levels of angiotensin II (ICU patients vs. controls: 1.2 ± 1.0 vs. 2.0 ± 1.1 fmol/m; P< 0.05), aldosterone (235.1 ± 145.1 vs. 284.4 ± 181.4 pg/mL; P=NS), renin (20.0 ± 22.4 vs 19.7 ± 13.2 pg/mL; P=NS) or serum level of TREM-1 (ICU patients vs. ICU septic shock unrelated to Covid-19: 265.3 ± 161.2 vs 608 ± 338.3 pg/mL; P< 0.05) ruled out any hyper-activation of the renin-angiotensin-aldosterone system or the leucocyte respiratory burst in ICU Covid-19 patients, contrary to septic patients. Electron microscopy illustrated irregular aspect of the endothelial wall due to fibrillar network of fibrin depots and damaged but viable endothelial cells responsive to circulating autacoids. Conclusion: Endothelial oxidative stress with ensuing decreased NO bioavailability appears as a key pathogenic factor of endothelial dysfunction and respiratory failure in ICU Covid-19 patients that, contrary to septic shock is not associated with an overactivation of the renin-angiotensin-aldosterone system or leucocyte respiratory burst. These results highlight an urgent need for oriented research leading to a better understanding of the specific endothelial oxidative stress that occurs during SARS-CoV-2.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Endothelial function; COVID-19; Oxidative stress; Thrombosis; Angiotensin II16049: Fatty Acid-Binding Proteins Control Endothelial Cells GlycolysisBin Liu, Shuai Li, Dan Yi, Jiakai Pan, Rebecca Li, Zhiyu Dai; 1Univ of Arizona, Phoenix, AZ,Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: We hypothesis that endothelial fatty acid metabolism is critical for obstructive vascular remodeling in the pathogenesis of PAH. Methods: Here we applied single-cell RNA sequencing (scRNA-seq) to profile the pulmonary cells in a severe mouse model (Egln1Tie2Cre mice) of PH. Human hPAEC from idiopathic PAH patients and healthy donors were used to measure fatty acid-binding protein 4 and 5 (FABP4 and FABP5) expression. siRNA mediated knockdown of FABP4 and FABP5 was performed to study cell proliferation and apoptosis. Glycolysis assay was performed to evaluate the role of FABP4-5 on ECs. Egln1Tie2Cre mice were bred with Fabp45-/- mice to generate Egln1Tie2Cre/Fabp45-/- mice. Results: scRNA-seq analysis demonstrated that both FABP4 and 5 were highly induced in the ECs of Egln1Tie2Cre mice. PAECs from IPAH patients also showed higher expression of FABP4 and 5. Knockdown of FABP4-5 reduced EC proliferation and starvation-induced Caspase 3/7 activity. Overexpression of FABP4-5 promoted EC glycolysis and proliferation. Genetic deletion of Fabp4 and 5 in Egln1Tie2Cre mice exhibited a reduction of RVSP, RV hypertrophy, and reduction of EC glycolysis gene programming compared to Egln1Tie2Cre mice. Conclusions: FABP4 and 5 control EC glycolysis and contribute to the development of PAH.This research has received full or partial funding support from the American Heart Association.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Pulmonary hypertension; Endothelial function; Lipoproteins; Glucose16640: Apob-100 Peptide Complexed To Nanoparticles as Therapeutic Modality in ASCVD: A Translational StudyKuang-yuh Chyu1, Xiaoning Zhao2, Jianchang Zhou3, Paul C Dimayuga1, Wai Man Lio4, Bojan Cercek1, Noah Trac5, Eun Ji Chung6, Prediman K Shah1; 1Cedars Sinai Med Cntr, Los Angeles, CA, 2Cedars Sinai Med Cntr, West Hollywood, CA, 3Cedars Sinai Med Cntr, W Hollywood, CA, 4Div of Cardiology, Cedars-Sinai Heart Institute, Cedars-Sinai Med Cntr, Los Angeles, CA, 52Dept of Biomedical Engineering, Univ of Southern California, Los Angeles, CA, 6Univ of Southern California, Los Angeles, CA,Introduction: ApoB-100 peptides provoke self-reactive immune responses in patients with atherosclerotic cardiovascular disease (ASCVD). It is unclear if there is a specific T cell memory population that responds to apoB-100 self-antigens and if it is modifiable. The use of self-peptides complexed to nanoparticles is under investigation as therapy to modulate immune self-reactivity in autoimmune disease. In this study, we assessed: 1) the intrinsic T Effector and T Effector Memory (TEM) response to the apoB-100 peptide P210 previously reported to generate self-reactive immune responses in ASCVD patients; and 2) the translational potential of P210-complexed to peptide amphiphile micelle (PAM) nanoparticles in reducing atherosclerosis in humanized Class-I MHC HLA-A*0201 chimeric mice on the apoE-/- background, developed in our laboratory. Methods and results: PBMCs from ACS patients (N=13) stimulated with P210 resulted in persistent CD8+ T Effector and TEM response, with no difference in CD4+ T cells, compared to controls (N=14; P<0.05). We then tested if P210-PAM nanoparticles altered the intrinsic T cell response to P210. We postulated if the intrinsic response to P210 was not altered by P210-PAMs, then the T cell responses to P210 peptide alone should correlate with the T cell response to P210-PAM. CD4+ T cell response to P210 peptide and P210-PAM were correlated (Spearman r=0.94; P=0.02; N=6) but CD8+ T cell responses were not, suggesting P210 complexed to PAM may alter its immune reactivity with CD8. The potential for P210-PAM as immune-modulating therapy was tested in humanized hypercholesterolemic HLA-A*0201 mice which had similar immune profile, serum cholesterol and aortic atherosclerosis compared to non-transgenic littermates. P210-PAMs were administered in 3 subcutaneous injections 2-3 weeks apart in mice of both sexes. A mouse serum albumin (MSA) peptide served as control. There was significantly reduced aortic atherosclerosis (P<0.05) in mice treated with P210-PAM (N=13) compared to PBS-treated mice (N=14) and those treated with MSA-PAM (N=20). Conclusion: The results suggest that nanoparticle-based immune modulation of T cell responses to apoB-100 may have translational therapeutic potential against atherosclerosis in ASCVD.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Atherosclerosis; Immunology; Immune system17115: Salt-induced Blood Pressure Elevation In Females Is Associated With Increased Arachidonic Acid Metabolite Regulation Of ENaCJeanne A Ishimwe1, Evan C Ray2, Thomas R Kleyman3, Annet Kirabo4, Cheryl L Laffer5, Alp Ikizler6, Fernando Elijovich7; 1Vanderbilt Univ, VUMC, Nashville, TN, 2UPMC DIVISION OF NEPHROLOGY, Pittsburgh, PA, 3UNIVERSITY PITTSBURGH, Pittsburgh, PA, 4Vanderbilt Univ Med Cente, Nashville, TN, 5VANDERBILT U SCHOOL of MEDICINE, Nashville, TN, 6Nashville, TN, 7VANDERBILT UNIVERSITY, Nashville, TN,Studies on the impact of sex as a biological variable on salt sensitivity of blood pressure (SSBP) are controversial. While population studies show that women are more salt-sensitive than men, studies in rodents indicate the opposite. Epithelial sodium channel (ENaC) plays an important role in SSBP. Dendritic cells sense Na+ through ENaC leading to formation of Isolevuglandins and promoting inflammation and hypertension. The mechanistic interplay between excess dietary Na+ and the role of sex as a biological variable in SSBP is still yet to be defined. Arachidonic acid (AA) and its metabolites including Epoxyeicosatrienoic acids (EETs) play an important role in SSBP, the latter by regulating the activity of ENaC. We hypothesized that regulation of ENaC by EETs contributes to sex differences in SSBP. We performed plasma metabolomics analysis in volunteers whose blood pressure and Na+ intake were monitored. We classified Na+ intake <2.3g as normal salt, and ≥ 2.3g Na+ as high salt, based on the American Heart Association recommendations. We found that women (n=81) had a stronger relationship between BP and Na+ intake than men (n=49) (r=0.372; p<0.001 vs. r=0.317; p=0.026). Among the participants consuming high Na+, women (28) had higher levels of AA than men (25), (1.119 ± 0.242 vs. 0.965 ± 0.201; p=0.015) and 12-HETE (1.329± 0.925 vs. 0.902 ± 0.520; p=0.047). Using the Weinberger protocol to assess salt sensitivity in humans, we found that increased urine EETs were associated with greater reductions of isolevuglandins in human antigen-presenting cells following salt depletion. In a novel mouse strain, the W521R mouse that carries a gain-of-function mutation in ENaC, we found that males developed high salt-induced hypertension when fed a HS diet for 3 weeks compared to baseline (134.3±3.7 mmHg vs. 111.9±4.8 mmHg, p=0.01) which was not observed in their littermate controls (119.3±5.4mmHg vs. 108.8±3.7mmHg, p=0.162). No blood pressure changes were observed in female W521R mice (102.3± 5.23 vs. 109.5± 7.75, p= 0.467) or littermate controls (99.5± 1.87 vs. 105.3± 4.95, p=0. 0.296). Our findings further indicate a paradoxical effect of sex on SSBP in humans and mice and suggest a role of ENaC regulation by AA metabolites.Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2021 Online Program Planner and search for the abstract title.Key Words: Sex differences; Hypertension:experimentalLate-Breaking Basic Science: New Advances in Cardiovascular Metabolism and Disease16215: Angiotensin Converting Enzyme Inhibitor and Sodium Glucose Cotransporter Inhibitor Alleviate Inflammatory Effects Of SARS-CoV-2 in Human Induced Pluripotent Stem Cell-Derived CardiomyocytesChun Ka Wong, Yee-Man Lau, Kevin Lai, Ricky Ruiqi Zhang, Hayes Kam hei Luk, Antonio Cheuk Pui Wong, Patrick Chiu Yat Woo, Susanna Kar Pui Lau, Kwok Hung Chan, Ivan FN HUNG, Chung Wah Siu; 1Univ of Hong Kong, Hong Kong, Hong KongBackground: Amid COVID-19 pandemic, there have been concerns regarding safety of angiotensin-converting enzyme inhibitor (ACEi) and sodium-glucose cotransporter 2 inhibitor (SGLT2i). Methods and Results: We evaluated the effects of ACEi and SGLT2i pretreatment on human induced-pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) infected by SARS-CoV-2. HiPSC-CM were pretreated with ACEi o
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