Citation Information: JCI Insight. 2024;9(20):e184940. https://doi.org/10.1172/jci.insight.184940.
Abstract
Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1—the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen—is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary.
Authors
Le Phuong Nguyen, Wenxin Song, Ye Yang, Anh P. Tran, Thomas A. Weston, Hyesoo Jung, Yiping Tu, Paul H. Kim, Joonyoung R. Kim, Katherine Xie, Rachel G. Yu, Julia Scheithauer, Ashley M. Presnell, Michael Ploug, Gabriel Birrane, Hannah Arnold, Katarzyna Koltowska, Maarja A. Mäe, Christer Betsholtz, Liqun He, Jeffrey L. Goodwin, Anne P. Beigneux, Loren G. Fong, Stephen G. Young
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.181172.
Abstract
Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.
Authors
Mingjing Chen, Zhijie Huang, Guanhong Miao, Jin Ren, Jinling Liu, Mary J. Roman, Richard B. Devereux, Richard R. Fabsitz, Ying Zhang, Jason G. Umans, Shelley A. Cole, Tanika N. Kelly, Oliver Fiehn, Jinying Zhao
Abstract
Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B-cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr–/– mice resulted in hindered T- and B-cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels. However, despite markedly impaired peripheral proinflammatory Th1 cells and atheromatous CD4+ T cells, the unexpected net effect of hematopoietic PI3Kδ deficiency was aggravated vascular inflammation and atherosclerosis. Further analyses revealed that PI3Kδ deficiency impaired numbers, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs), whereas macrophage biology remained largely unaffected. Adoptive transfer of wild-type Tregs fully restrained the atherosclerotic plaque burden in Ldlr–/– mice lacking hematopoietic PI3Kδ, whereas PI3Kδ deficient Tregs failed to mitigate disease. Numbers of atheroprotective B-1 and proatherogenic B-2 cells as well serum immunoglobulin levels remained unaffected by adoptively transferred wild-type Tregs. In conclusion, we demonstrate that hematopoietic PI3Kδ ablation promotes atherosclerosis. Mechanistically, we identified PI3Kδ signaling as a powerful driver of atheroprotective Treg responses, which outweigh PI3Kδ driven proatherogenic effects of adaptive immune cells like Th1 cells.
Authors
Mario Zierden, Eva Maria Berghausen, Leoni Gnatzy-Feik, Christopher Millarg, Felix Simon Ruben Picard, Martha Kiljan, Simon Geißen, Apostolos Polykratis, Lea Zimmermann, Richard Julius Nies, Manolis Pasparakis, Stephan Baldus, Chanil Valasarajan, Soni Savai Pullamsetti, Holger Winkels, Marius Vantler, Stephan Rosenkranz
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.182599.
Abstract
Circadian time-of-intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its co-factor, Krüppel-like factor (Klf15), play critical roles in maintaining normal heart function in the long-term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of GR-Klf15 axis remain undefined. Here, we demonstrate the critical roles of the cardiomyocyte-specific GR and Klf15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or Klf15, we identified their synergistic role in the activation of adiponectin receptor expression (Adipor1) and the mitochondrial pyruvate complex (Mpc1/2), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic (db/db) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, effectively restored cardiomyocyte glucose oxidation and improved diastolic function towards control-like levels in a sex-independent manner. Collectively, our findings uncover novel cardiomyocyte-autonomous metabolic targets of the GR-Klf15 axis. This study highlights the circadian-dependent cardioprotective effects of glucocorticoids on cardiomyocyte glucose metabolism, providing critical insights into chrono-pharmacological strategies for glucocorticoid therapy in cardiovascular disease.
Authors
Hima Bindu Durumutla, Ashok Prabakaran, Fadoua El Abdellaoui Soussi, Olukunle Akinborewa, Hannah Latimer, Kevin McFarland, Kevin Piczer, Cole Werbrich, Mukesh K. Jain, Saptarsi M. Haldar, Mattia Quattrocelli
Citation Information: JCI Insight. 2024;9(16):e177152. https://doi.org/10.1172/jci.insight.177152.
Abstract
Friedreich’s ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide–positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not “fail” per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.
Authors
Caroline E. Perry, Sarah M. Halawani, Sarmistha Mukherjee, Lucie V. Ngaba, Melissa Lieu, Won Dong Lee, James G. Davis, Gabriel K. Adzika, Alyssa N. Bebenek, Daniel D. Bazianos, Beishan Chen, Elizabeth Mercado-Ayon, Liam P. Flatley, Arjun P. Suryawanshi, Isabelle Ho, Joshua D. Rabinowitz, Suraj D. Serai, David M. Biko, Jaclyn Tamaroff, Anna DeDio, Kristin Wade, Kimberly Y. Lin, David J. Livingston, Shana E. McCormack, David R. Lynch, Joseph A. Baur
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.180906.
Abstract
The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
Authors
Joseph R. Visker, Ahmad A. Cluntun, Jesse N. Velasco-Silva, David R. Eberhardt, Luis Cedeno-Rosario, Thirupura S. Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J. Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S. Ducker, Stavros G. Drakos, Jared Rutter
Abstract
Little is known about the expression patterns and functions of circular RNAs (circRNAs) in the heart of large mammals. In this study, we examined the expression profiles of circRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in neonatal pig hearts. Pig heart samples collected on postnatal days 1 (P1), 3 (P3), 7 (P7) and 28 (P28) were sent for total RNA sequencing. Our data revealed a total of 7000 circRNAs in the 24 pig hearts. Pathway enrichment analysis of hallmark gene sets demonstrated that differentially expressed circRNAs are engaged in different pathways. The most significant difference was observed between P1 and the other three groups (P3, P7 and P28) in pathways related to cell cycle and muscle development. Out of the ten circRNAs that were validated through real-time quantitative polymerase chain reaction (qRT-PCR) to confirm their expression, six exhibited significant effects on cell cycle activity in human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) following small interfering RNA-mediated knockdown. The circRNA-miRNA-mRNA networks were constructed to understand the potential mechanisms of circRNAs in the heart. In conclusion, our study provided a dataset for exploring the roles of circRNAs in pig hearts. In addition, we identified several circRNAs that regulate cardiomyocyte cell cycle.
Authors
Ling Tang, Nyarige Verah, Pengsheng Li, Junwen Wang, Wuqiang Zhu
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.171102.
Abstract
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by Clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, mitoTEMPO, and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.
Authors
Xiaoxu Zhou, Hong Liu, Feng Feng, Gyeoung-Jin Kang, Man Liu, Yugene Guo, Samuel C. Dudley Jr.
Citation Information: JCI Insight. 2024. https://doi.org/10.1172/jci.insight.181042.
Abstract
Parasympathetic dysfunction after chronic myocardial infarction (MI) is known to predispose ventricular tachyarrhythmias (VT/VF). VT/VF after MI is more common in males than females. The mechanisms underlying the decreased vagal tone and the associated sex difference in the occurrence of VT/VF after MI remain elusive. In this study, using optogenetic approaches, we found that responses of glutamatergic vagal afferent neurons were impaired following chronic MI in male mice, leading to reduced reflex efferent parasympathetic function. Molecular analyses of vagal ganglia demonstrated reduced glutamate levels, accompanied by decreased mitochondrial function and impaired redox status in infarcted males vs. sham animals. Interestingly, infarcted females demonstrated reduced vagal sensory impairment, associated with greater vagal ganglia glutamate levels and decreased vagal mitochondrial dysfunction and oxidative stress compared to infarcted males. Treatment with 17β-estradiol mitigated this pathological remodeling and improved vagal neurotransmission in infarcted male mice. These data suggest that a decrease in efferent vagal tone following MI results from reduced glutamatergic afferent vagal signaling that may be due to impaired redox homeostasis in the vagal ganglia, which subsequently leads to pathological remodeling in a sex-dependent manner. Importantly, estrogen prevents pathological remodeling and improves parasympathetic function following MI.
Authors
Asokan Devarajan, Ke Wang, Zulfiqar A. Lokhandwala, Maryam Emamimeybodi, Kassandra Shannon, John D. Tompkins, Andrea L. Hevener, Aldons J. Lusis, E. Dale Abel, Marmar Vaseghi
Citation Information: JCI Insight. 2024;9(11):e171005. https://doi.org/10.1172/jci.insight.171005.
Abstract
TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant using CRISPR editing. Our natural history study in patients with TDD suggests that the intake of multivitamin/B complex greatly diminished the risk of cardiac crises in patients with TDD. In agreement with the clinical findings, we demonstrated that high-dose folate (vitamin B9) virtually abolishes arrhythmias in TDD iPSC-CMs and that folate’s effect was blocked by the dihydrofolate reductase inhibitor methotrexate, supporting the need for intracellular folate to mediate antiarrhythmic effects. In summary, data from TDD iPSC-CM models together with clinical observations support the use of B vitamins to mitigate cardiac crises in patients with TDD, providing potentially life-saving treatment strategies during life-threatening events.
Authors
Weiyi Xu, Yingqiong Cao, Sara B. Stephens, Maria Jose Arredondo, Yifan Chen, William Perez, Liang Sun, Andy C. Yu, Jean J. Kim, Seema R. Lalani, Na Li, Frank T. Horrigan, Francisco Altamirano, Xander H.T. Wehrens, Christina Y. Miyake, Lilei Zhang
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