tbuckley/cabot-search huggingface dataset:
Abstract Tu093: Adeno-associated virus-mediated gene delivery of PERM1 enhances cardiac contractility and mitochondrial biogenesis in mice.
Authors: KARTHI SREEDEVI, Abigail Oforiwaa Doku, Amina James, Sara Do, Alexey Zaitsev, Junco Warren
Journal: Circulation Research (2024)

Heart failure remains the leading cause of death in the U.S., and 50% of patients with heart failure still die within 5 years after diagnosis. Mitochondrial impairment and contractile dysfunction are the hallmarks of heart failure with reduced ejection fraction (HFrEF). Yet, there is currently no therapeutic strategy targeting both mitochondria and muscle contractility. PERM1 is a striated-muscle-specific regulator of mitochondrial bioenergetics and is predominantly expressed in the heart and skeletal muscle. Our recent studies demonstrated that PERM1 is downregulated in human and mouse HFrEF hearts and that loss of PERM1 in mice leads to reduced contractility and energy reserve in the heart. However, it is largely unknown whether PERM1 positively regulates both muscle contractility and energetics in the heart. Here, we performed the gene delivery of Perm1 to the heart in C57BL6 wild-type mice (8-12 weeks old) through retro-orbital injection of the adenovirus-associated virus (AAV)9 vector carrying Perm1 (AAV-PERM1). The protein expression levels of PERM1 in the heart was increased by 3 fold as compared with control (mice injected with AAV9-GFP vectors), while there was no change in PERM1 expression in skeletal muscle (n=4/group). Strikingly, AAV-PERM1 mice exhibited a significant increase in ejection fraction (EF) and fractional shortening (FS) (AAV-GFP vs. AAV-PERM1: 0.93 vs. 1.43 and 0.92 vs. 1.64 in DEF and DFS, respectively, both p&lt;0.05 in t-test). In addition, we observed a subtle, yet significant increase in the ratio of the heart weight to tibial length in AAV-PERM1 mice (AAV-GFP vs. AAV-PERM1: 4.7 vs 5.97, p&lt;0.05 in t-test), suggestive of moderate cardiac hypertrophy development. Furthermore, PERM1 overexpression in the heart increased the mitochondrial copy number by 38% as compared to control AAV-GFP mice (p&lt;0.05 in t-test), concurrently with an upregulation of the mitochondrial bioenergetics master regulator PGC-1α (155% of control, p&lt;0.05 in t-test). Overall, these results showed that AAV-mediated PERM1 overexpression simultaneously enhances muscle contractility and mitochondrial biogenesis in the heart. This study further suggests that the gene delivery of PERM1 could be a potential therapeutic approach to treat HFrEF patients.
Abstract Tu014: Endoplasmic reticulum stress exacerbates atherosclerosis via microRNA-181a by inhibiting mitophagy
Authors: Lingjun Wang, Yanhong Cao, xin chen
Journal: Circulation Research (2024)

Introduction: Atherosclerosis is a chronic and progressively advancing vascular disease, which ultimately leads to the hardening and narrowing of blood vessel walls, significantly increasing the risk of cardiovascular events such as heart attacks and strokes. Within plaques, macrophages undergo endoplasmic reticulum stress(ERS) in response to lipid stimulation, directly impacting mitochondrial function. Mitophagy serves as the primary pathway for macrophages to clear damaged mitochondria. However, the relationship between endoplasmic reticulum stress in macrophages and mitophagy remains unclear. Hypothesis: there exists a regulatory relationship between endoplasmic reticulum stress and mitophagy in macrophages. Objective: To study the effect of endoplasmic reticulum stress on mitophagy and its mechanism in atherosclerosis. Methods: To investigate the effect of ERS on mitochondrial autophagy, we specifically inhibited IRE1α activity in vivo, followed by testing atherosclerosis plaque and mitophagy. To explore the mechanism by which endoplasmic reticulum stress acts on mitophagy, we detected miRNAs by qPCR. The Binding of Inositol-requiring enzyme 1(IRE1α) to miRNA was detected by RNA Binding Protein Immunoprecipitation Assay (RIP). We verified miRNA’s effect on regulating mitophagy by knocking down or over expressing miRNA in vivo. To find the downstream mechanism, we predicted and verified the target gene and testified the signaling pathway by rescue experiments. Results: IRE1α RNase activity inhibition lightened atherosclerosis but upregulated miRNA181a and mitophagy level. In vivo, overexpressing miRNA181a reduced atherosclerosis plaque and enhanced mitophagy; results were reversed when knocking down miRNA181a. Overexpressing or silencing target gene in vitro, mitophagy is correspondingly inhibited or promoted. Conclusion: In atherosclerosis, endoplasmic reticulum stress increases, resulting in inhibition of mitophagy. IRE1 α further increases its target gene JNK by shearing pre-miRNA181, thereby inhibiting the expression of miRNA181a. The over expression of JNK eventually upregulated the JNK-c-JUN-Parkin signaling pathway, aggravating atherosclerosis. These results provided new data for the mechanism of endoplasmic reticulum stress on atherosclerosis.
Abstract Tu001: MiR-21 mitigated pulmonary hypertension induced right ventricular dysfunction through pulmonary circulating exosomes
Authors: Wei-Ting Chang, Sudeshna Fisch, Chih-Hsin Hsu
Journal: Circulation Research (2024)

Background: Patients with pulmonary arterial hypertension (PAH) often experience adverse outcomes primarily due to right ventricular (RV) dysfunction. However, the intricate relationship between pulmonary circulation and RV remodeling remains largely unexplored. Exosomal microRNAs (miRNAs) function as paracrine signaling mediators in diverse diseases. Aims: To investigate the ability of exosomal miRNAs derived from pulmonary endothelial cells to transmit signals affecting cardiomyocytes. Methods and Results: Utilizing next-generation sequencing, we identified several target miRNAs by analyzing exosome samples obtained through right-heart catheterization. Notably, exosomal miR-21 exhibited the highest expression in the pulmonary circulation (Figure 1) . Under hypoxic conditions, the expression of miR-21 increased in human pulmonary endothelial cells (HPECs) and in exosomes derived from their conditioned medium. Treatment with these exosomes enhanced miR-21 expression and concurrently mitigated apoptosis in hypoxia-exposed cardiomyocytes. Likewise, miR-21 demonstrated a protective role against hypoxia-induced injuries and apoptosis, involving the SPRY-2/p-ERK and PTEN/Akt pathways. In a murine model of sugen/hypoxia-induced PAH, mice lacking miR-21 (miR-21 -/- ) exhibited more severe RV dysfunction, altered hemodynamics, and increased fibrosis compared to wild-type (WT) mice. Employing a parabiosis model, pairs consisting of WT and miR-21 -/- mice were shielded from RV dysfunction, whereas pairs of miR-21 -/- mice displayed exacerbated RV function (Figure 2) . Conclusion: Hypoxia stimulates the production of exosomal miR-21 in both HPECs and their microenvironment, subsequently mitigating apoptosis in cardiomyocytes (Figure 3) . Our findings propose endothelial cell-derived exosomal miR-21 as a promising therapeutic target for PAH.
Abstract Tu065: The role of heavy metals in pulmonary arterial hypertension pathogenesis
Authors: Dakotah Cathey, Lu Cai, Jun Cai, YI TAN, Jiapeng Huang
Journal: Circulation Research (2024)

Pulmonary arterial hypertension (PAH) is a disease where chronic high pulmonary arterial pressure causes inflammation, remodeling, and dysfunctions of lung endothelial/smooth muscle cells, and right ventricle (RV) cardiomyocytes. Pathogenesis is caused by a mixture of genetic, epigenetic, and environmental factors. Our clinical studies found PAH patients had elevated cadmium (Cd) and antimony (Sb) levels in the blood and/or urine, which correlated with increased severity of PAH parameters. Thus, we hypothesize that environmental factors, specifically chronic heavy metal exposure, could contribute to PAH pathogenesis either directly or indirectly. We tested if Cd could induce PAH or worsen PAH parameters in the mouse SU5416 and hypoxia (SuHx) PAH model. Forty male C57/6J mice were initially split in 2 groups: control and 5ppm Cd in drinking water (n=20/each) for 8 weeks (wks). Diastolic and systolic functions were evaluated with echocardiography (echo) at baseline, and 8ks. Then, half of these mice were subject to PAH induction, netting 4 subgroups (n=10/group): CTRL, Cd, PAH, and Cd+PAH. Echo was performed again 4 wks post-PAH induction, followed by RV systolic pressure (RVSP) measurement (n=3/group). The remaining 7 mice/group were euthanized for heart/lung histopathology focusing on fibrosis and hypertrophy, and protein western blot analyses. GraphPad Prism 8 software was used for statistical analysis with normality checked. When data did not follow normality, the non-parametric equivalence was used. Two-way and one-way ANOVA with Tukey were performed for echo/RVSP and histological/biochemical analyses respectively, with a p-value&lt;0.05 being significant. Results showed 12-wks Cd exposure alone caused: (1) significantly increased RV systolic function indicating systolic stimulation, and (2) significantly increased collagen contents in both ventricles and LV cardiomyocyte area when compared to CTRL. Twelve-wks Cd+PAH group demonstrated (1) significantly decreased RV cardiac output and RVSP measurements indicating RV failure; (2) no further RV changes in collagen contents or hypertrophy; (3) LV western blot analysis revealed significant upregulation of antioxidant proteins, including catalase and superoxide dismutase 2, when compared to PAH group. Further mechanistic experiments are being conducted, including whether Sb has similar results as Cd.
Abstract Mo102: Swine Model of Heart Failure with Preserved Ejection Fraction Driven by Lipoprotein Lipase Inhibition and Enhanced Cardiac Low-Density Lipoprotein Receptor Expression
Authors: Jose Manuel Condor, Emely Robleto, Luiza Bagno, Simona Ionescu, Diana Clavellina, Marcos Rosado, Jose Rodriguez, Ali Saad, Lauro Takeuchi, Wayne Balkan, KEITH WEBSTER, Joshua Hare, Lina Shehadeh
Journal: Circulation Research (2024)

Background: Heart failure with preserved ejection fraction (HFpEF) poses an escalating public health threat, marked by growing incidence and high mortality. In the cardiometabolic phenogroup of HFpEF that includes diabetes and obesity, intramyocardial lipid content is a prognostic indicator of diastolic dysfunction and adverse outcome. Our group recently reported a mouse model of cardiometabolic HFpEF wherein myocardial lipotoxicity was induced by systemic inhibition of lipoprotein lipase (LPL) with Poloxamer 407 (P407) and cardiac overexpression of the LDL receptor (LDLR), conditions that have been documented in clinical HFpEF. The model demonstrates myocardial lipid accumulation, fibrosis, arrhythmia, and diastolic dysfunction. To reproduce this model in large animals we implemented the same protocol in pigs. Methods: Female Yorkshire swine (~25 Kg) were subjected to one of two protocols including: 1) single intracoronary (i.c.) injection of 10 13 AAV9-cTnT-LDLR particles and biweekly intraperitoneal (i.p.) P407 at 1g/Kg, (high dose, n=2), or 2) Double i.c. injections of 10 13 AAV9-cTnT-LDLR particles and biweekly i.p. P407 at 0.25g/Kg) (low dose, n=2). Cardiac structure and function were evaluated by MRI, and hemodynamics measured by PV-Loop at baseline, 4, 8, and 12 weeks. Blood was collected biweekly for complete blood count (CBC), basic biochemistry, and liver and lipid panels. Tissues were collected for protein and histopathological analysis. Results: In both strategies, the animals developed high LDL-cholesterol and cardiac hypertrophy with preserved EF. High dose P407 led to higher triglycerides, VLDL, HDL, liver injury (ALT &gt; 200U/L), and steatosis at 4 weeks. One of the 2 pigs died at 3 weeks. Low dose P407 and high dose viral particles induced HFpEF at ~12 weeks with increased LV mass, relative wall thickness, end-diastolic pressure, and tau. Serum LDL-C accumulated from an initial value of 161 to 344.5mg/dL at 12 weeks. No significant liver injury was present until week 12 (ALT&lt;88 U/L, AST&lt;59 U/L). Both strategies did not exhibit abnormalities in CBC or other biochemical parameters. Conclusions: Low dose inhibition of LPL combined with cardiac overexpression of LDLR confers HFpEF in swine.
Abstract Mo105: End Systolic Pressure and Ejection Timing Correlate with Impaired Relaxation
Authors: Yoshio Wagner, Charles Chung
Journal: Circulation Research (2024)

Impaired relaxation is a common feature in most cases of diastolic dysfunction, including heart failure with preserved ejection fraction. Isovolumetric relaxation is typically characterized by τ, an exponential time constant, but may be broken into relaxation and stiffness-like parameters (µ and Ek). Recent in vitro work suggests that strain during late systole (protodiastolic period) modifies relaxation. We hypothesize that late systolic pressure and time indexes correlate with myocardial relaxation. Thirty-four (34) simultaneous aortic and left ventricular micromanometric (Millar) pressure traces were obtained from a comprehensive database of clinical cardiac catheterization patients. These patients underwent coronary artery disease screening and presented but did not have arterial blockages. Pressure and time parameters were calculated over a five-minute interval. Relaxation rate (1/τ), and stiffness (Ek) correlated to end systolic parameters in an orthogonal pattern to relaxation (µ). 1/τ showed strong correlations with time from peak pressure to aortic valve divided by ejection time (t54/t52, r = .675, p &lt; .01) and moderate correlation to the pressure decline after peak pressure to aortic valve pressure divided by the pulse pressure (P45/P42, r = .577, p &lt; .01). In parallel Ek showed moderate correlation with t54/t52 (r = .592, p &lt; .01), and a moderate correlation with P45/P42 (r = .470, p &lt; .01), the pressure at aortic valve closure (r = -.420, p &lt; .05), and aortic augmentation index (AIx, r = -.360, p &lt; .05). Finally, µ presented a moderate correlation to P45/P42 (r = .501, p &lt; .05), the pressure at aortic valve closure (r = .404, p &lt; .05), and AIx (r = -.357, p &lt; .05). As predicted, ventricular relaxation in patients correlates with late systolic hemodynamics. Parameters or combinations of parameters may predict relaxation rates or correlate to in vivo late systolic strain. Prospective studies evaluating end systolic strain and relaxation merit consideration. Overall, these observations are consistent with in vitro studies that suggest that impaired cessation of contraction is a regulator of relaxation.
Abstract Tu089: p21 Regulates Hypertrophic Cardiomyopathy Remodeling By Inhibition of Cardiomyocyte Endoreplication
Authors: Soumojit Pal, Michael Glennon, Benjamin R. Nixon, Ethan Chetkof, Puneeth Shridhar, Chintha M. Kathiresan, Nicolas CLAVERE, Dipanjan Banerjee, Jason Becker
Journal: Circulation Research (2024)

Background: We previously discovered that a murine model of hypertrophic cardiomyopathy had increased cardiomyocyte endoreplication and replication stress leading to increased DNA damage. Activation of DNA damage response pathways was associated with increased cardiomyocyte expression of the cyclin-dependent kinase inhibitor p21. However, the role of p21 on pathologic myocardial remodeling in hypertrophic cardiomyopathy is poorly understood. Methods: We utilized a murine model of hypertrophic cardiomyopathy that is deficient in cardiac myosin binding protein 3 (Mybpc3 -/- ). We used murine models deficient in p21 (Cdkn1a -/- ) or overexpressed p21 (Cdkn1a SUPER ) to determine the role of p21 on hypertrophic remodeling. Heart structure and function were evaluated by echocardiography. Flow cytometry and immunohistochemistry were used to measure cardiomyocyte DNA content and ploidy. Proteomics and biochemical assays were utilized to identify p21 target proteins. Results: We observed that there was an increased p21 expression in Mybpc3 -/- cardiomyocytes during the postnatal day 7 to 25 time interval. Elimination of p21 expression in Mybpc3 -/- animals (Cdkn1a -/- /Mybpc3 -/- ) caused increased myocardial hypertrophy (Table 1). Conversely, selective overexpression of p21 in cardiomyocytes (Cdkn1a SUPER /Mybpc3 -/- /Myh6Cre) led to reduced myocardial hypertrophy (Table 1). We discovered that isolated cardiomyocyte nuclei from Mybpc3 -/- mice with reduced p21 had increased polyploidy whereas overexpression of cardiomyocyte p21 led to reduced cardiomyocyte polyploidy (Table 1). Using both proteomics and targeted assays we discovered that cardiomyocyte p21 was binding to key cycle regulatory proteins to inhibit cardiomyocyte endoreplication and hypertrophic growth. Conclusions: Collectively, our results show that induction of p21 in hypertrophic cardiomyopathy reduces cardiomyocyte growth by inhibiting endoreplication.
Abstract Mo030: Deep learning based multi-omics model for prediction of outcomes in HFpEF and HFmrEF
Authors: Sudeshna Fisch, Alokkumar Jha
Journal: Circulation Research (2024)

Introduction: Heart failure with preserved ejection fraction (HFpEF) presents a unique challenge in cardiology due to its diverse etiology and clinical presentation. Our study introduces a cutting-edge integrated deep learning model that combines multi-dimensional datasets, encompassing genetic variants from GWAS, cardiac structural and functional assessments from MRI, and electrophysiological data from ECGs, along with comorbidity profiles including CKD and LFT. Research Questions: Can a deep learning model that integrates multi-dimensional datasets accurately predict HFpEF risk? How does the inclusion of different types of data (genetic, MRI, comorbidity) affect the model's predictive accuracy? Goals: To develop a deep learning model that accurately predicts HFpEF risk To assess the impact of different types of data on the model's predictive accuracy. Methods: The model employs a graph convolutional multi-model deep learning approach to dissect the intricate interplay between genetic variants from GWAS, cardiac structural and functional assessments from MRI, electrophysiological data from ECGs, and comorbidity profiles including CKD and LFT. Results: The baseline genetic model achieved a PRS of 2.04 and an outcome accuracy of 81%. The incorporation of MRI features improved the outcome accuracy to 85.91%. The inclusion of comorbidities such as CKD and T2D resulted in the highest outcome accuracy of 88.57%. Discussion: The results suggest that the inclusion of MRI features and comorbidities improves the model's predictive accuracy. This model holds significant promise for clinical adoption and the advancement of personalized treatment strategies.
Abstract Tu118: The Mitochondrial LonP1 Is Indispensable For Cardiac Maturation And Function
Authors: Sakthijothi Muthu, Zinnia Tran, Kienan ODwyer, Sanketh Guppi, Subhankhi Pal, Murugesan Velayutham, Ethan Meadows, John Hollander, Venkatesh Sundararajan
Journal: Circulation Research (2024)

Background: LonP1 is a major mitochondrial ATP-dependent protease critical for mitochondrial protein quality control, However its role in cardiac function is unclear. Hypothesis: We hypothesize that LonP1 is essential for postnatal cardiac maturation and function. Methods: We employed cardiac-specific LonP1 knock-out (LonP1cKO) and Cre-control mice, assessing their heart histology (HE, trichrome), cardiac function via echocardiography, mitochondrial function by measuring oxygen consumption rate (OCR), mitochondrial complexes (I-V) activity by (ETC complex maximal activity), Iron-Sulfur (Fe-S) clusters and free radical levels by electron paramagnetic resonance (EPR) spectroscopy. The significant difference between the groups was established at p&lt;0.05 using the Student's 't' test. Results: We found that LonP1cKO mice were not embryonically lethal; however, they exhibited an early mortality rate, died at an average of 21 days after birth with significantly lower body weight (7.02±0.16 gm vs. control (11.41±0.25 gm), p&lt;0.0001, n=24) and increased heart weight to the tibia length ratio (0.080±0.002 gm/cm vs. control (0.047±0.0014 gm/cm), p&lt;0.001, n=24). Echocardiography analysis showed that LonP1ckO mice had severely decreased left ventricular ejection fraction (%EF) (14.06±1.82% vs. control (70±2.9%), p&lt;0.0001, n=16) and fractional shortening (% FS) (6.05±0.8% vs. control (39.15±2.5%), p&lt;0.0001, n=16). Histological analysis revealed severe ventricular dilation and increased cardiac fibrosis. Transmission electron microscope analysis showed a significant loss of cristae and accumulation of electron-dense aggregation within mitochondria of LonP1cKO but not in control mice. In addition, LonP1cKO hearts showed reduced Fe-S clusters level (10.70±0.85 a.u vs. 21.27±1.91, p&lt;0.0001, n=6), complex I-V activities (p&lt;0.001), and electron flow (152.2±4.04 nm/min/mg vs. 265.3±23.8, p&lt;0.001, n=6) compared to control. Conclusion: Our findings indicate that the deletion of LonP1 makes the heart unable to transition from glycolysis to substrate oxidation during the early postnatal maturation process, leading to dilated cardiomyopathy and death. This highlights the pivotal role of LonP1 in both cardiac maturation and function.
Abstract Tu094: p53 Regulates the Extent of Fibroblast Proliferation and Fibrosis in Left Ventricle Pressure Overload
Authors: Xiaoyi Liu, Ryan Burke, Janet Lighthouse, Cameron Baker, Ronald Dirkx, Brian Kang, Yashoswini Chakraborty, deanne mickelsen, jennifer twardowski, Stephano mello, John ashton, Eric Small
Journal: Circulation Research (2024)

Background: Cardiomyopathy is characterized by the pathological accumulation of resident cardiac fibroblasts that deposit ECM (extracellular matrix) and generate a fibrotic scar. However, the mechanisms that control the timing and extent of cardiac fibroblast proliferation and ECM production are not known, hampering the development of antifibrotic strategies to prevent heart failure. Methods: We used the Tcf21 (transcription factor 21) MerCreMer mouse line for fibroblast-specific lineage tracing and p53 (tumor protein p53) gene deletion. We characterized cardiac physiology and used single-cell RNA-sequencing and in vitro studies to investigate the p53-dependent mechanisms regulating cardiac fibroblast cell cycle and fibrosis in left ventricular pressure overload induced by transaortic constriction. Results: Cardiac fibroblast proliferation occurs primarily between days 7 and 14 following transaortic constriction in mice, correlating with alterations in p53-dependent gene expression. p53 deletion in fibroblasts led to a striking accumulation of Tcf21- lineage cardiac fibroblasts within the normal proliferative window and precipitated a robust fibrotic response to left ventricular pressure overload. However, excessive interstitial and perivascular fibrosis does not develop until after cardiac fibroblasts exit the cell cycle. Single-cell RNA sequencing revealed p53 null fibroblasts unexpectedly express lower levels of genes encoding important ECM proteins while they exhibit an inappropriately proliferative phenotype. in vitro studies establish a role for p53 in suppressing the proliferative fibroblast phenotype, which facilitates the expression and secretion of ECM proteins. Importantly, Cdkn2a (cyclin-dependent kinase inhibitor 2a) expression and the p16Ink4a-retinoblastoma cell cycle control pathway is induced in p53 null cardiac fibroblasts, which may eventually contribute to cell cycle exit and fulminant scar formation. Conclusions: This study reveals a mechanism regulating cardiac fibroblast accumulation and ECM secretion, orchestrated in part by p53-dependent cell cycle control that governs the timing and extent of fibrosis in left ventricular pressure overload.