Cardiology
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
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
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.
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
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
Abstract
Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae–induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.
Authors
Haoyu Deng, Wan Yi Liang, Le Qi Chen, Tin Ho Yuen, Basak Sahin, Dragoș M. Vasilescu, Mark Trinder, Keith Walley, Patrick C.N. Rensen, John H. Boyd, Liam R. Brunham
Abstract
The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected >5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may impact cardiac contractility.
Authors
Colleen M. Kelly, Jody L. Martin, Michael J. Previs
Abstract
Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage–enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
Authors
Xiaohong Wang, Wa Du, Yutian Li, Hui-Hui Yang, Yu Zhang, Rubab Akbar, Hannah Morgan, Tianqing Peng, Jing Chen, Sakthivel Sadayappan, Yueh-Chiang Hu, Yanbo Fan, Wei Huang, Guo-Chang Fan
Abstract
Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during myocardial ischemia is well-studied, but the role of aerobic glycolysis during the early phase of reperfusion is incompletely understood. Lactylation of Histone H3 (H3) is an epigenetic indicator of the glycolytic switch. Heat shock protein A12A (HSPA12A) is an atypic member of the HSP70 family. In the present study, we report that during reperfusion following myocardial ischemia, HSPA12A was downregulated and aerobic glycolytic flux was decreased in cardiomyocytes. Notably, HSPA12A knockout in mice exacerbated MI/R-induced aerobic glycolysis decrease, cardiomyocyte death, and cardiac dysfunction. Gain- and loss-of-function studies demonstrated that HSPA12A was required to support cardiomyocyte survival upon hypoxia/reoxygenation (H/R) challenge, and that its protective effects were mediated by maintaining aerobic glycolytic homeostasis for H3 lactylation. Further analyses revealed that HSPA12A increased Smurf1-mediated Hif1α protein stability, thus increasing glycolytic gene expression to maintain appropriate aerobic glycolytic activity to sustain H3 lactylation during reperfusion, and ultimately improving cardiomyocyte survival to attenuate MI/R injury.
Authors
Wansu Yu, Qiuyue Kong, Surong Jiang, Yunfan Li, Zhaohe Wang, Qian Mao, Xiaojin Zhang, Qianhui Liu, Pengjun Zhang, Yuehua Li, Chuanfu Li, Zhengnian Ding, Li Liu
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