Publications by authors named "Roberta A Gottlieb"

157 Publications

Myocardial ultrastructure can augment genetic testing for sporadic dilated cardiomyopathy with initial heart failure.

ESC Heart Fail 2021 Sep 6. Epub 2021 Sep 6.

Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.

Aims: The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing.

Methods And Results: Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033).

Conclusions: Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.
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http://dx.doi.org/10.1002/ehf2.13596DOI Listing
September 2021

Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy.

Int J Mol Sci 2021 Aug 13;22(16). Epub 2021 Aug 13.

Cedars-Sinai Medical Center, Smidt Heart Institute, Beverly Hills, CA 90048, USA.

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.
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http://dx.doi.org/10.3390/ijms22168711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395861PMC
August 2021

Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

JCI Insight 2021 Sep 22;6(18). Epub 2021 Sep 22.

Department of Pediatrics, Division of Infectious Diseases and Immunology.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.
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http://dx.doi.org/10.1172/jci.insight.151981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492304PMC
September 2021

Hypothermia promotes mitochondrial elongation In cardiac cells via inhibition of Drp1.

Cryobiology 2021 Oct 29;102:42-55. Epub 2021 Jul 29.

Cedars-Sinai Smidt Heart Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32 °C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32 °C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.
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http://dx.doi.org/10.1016/j.cryobiol.2021.07.013DOI Listing
October 2021

Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress.

Mol Cancer Res 2021 Aug 16;19(8):1375-1388. Epub 2021 Apr 16.

Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars Sinai Medical Center, Los Angeles, California.

Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. IMPLICATIONS: This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349847PMC
August 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

At the heart of mitochondrial quality control: many roads to the top.

Cell Mol Life Sci 2021 Apr 5;78(8):3791-3801. Epub 2021 Feb 5.

Smidt Heart Institute, Cedars-Sinai Medical Center, AHSP9313, 127 S. San Vicente Blvd., Los Angeles, CA, 90048, USA.

Mitochondrial quality control depends upon selective elimination of damaged mitochondria, replacement by mitochondrial biogenesis, redistribution of mitochondrial components across the network by fusion, and segregation of damaged mitochondria by fission prior to mitophagy. In this review, we focus on mitochondrial dynamics (fusion/fission), mitophagy, and other mechanisms supporting mitochondrial quality control including maintenance of mtDNA and the mitochondrial unfolded protein response, particularly in the context of the heart.
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http://dx.doi.org/10.1007/s00018-021-03772-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106602PMC
April 2021

Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.
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http://dx.doi.org/10.1073/pnas.2015632118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817159PMC
January 2021

Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation.

Front Physiol 2020 6;11:950. Epub 2020 Aug 6.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitate-and linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK.
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http://dx.doi.org/10.3389/fphys.2020.00950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424056PMC
August 2020

Sensing Protein Quality in Cardiac Myocytes p62 Triggers a Lysosomal Response.

Circ Res 2020 07 30;127(4):519-521. Epub 2020 Jul 30.

Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA (R.A.G.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416846PMC
July 2020

Parkin, an E3 ubiquitin ligase, enhances airway mitochondrial DNA release and inflammation.

Thorax 2020 09 4;75(9):717-724. Epub 2020 Jun 4.

Department of Medicine, National Jewish Health, Denver, Colorado, USA

Introduction: Parkin (Park2), an E3 ubiquitin ligase, is critical to maintain mitochondrial function by regulating mitochondrial biogenesis and degradation (mitophagy), but recent evidence suggests the involvement of Parkin in promoting inflammation. In the present study, we determined if Parkin regulates airway mitochondrial DNA (mtDNA) release and inflammatory responses to type 2 cytokine interleukin (IL)-13 and allergens.

Methods: We measured Parkin mRNA expression in brushed bronchial epithelial cells and mtDNA release in the paired bronchoalveolar lavage fluid (BALF) from normal subjects and asthmatics. Parkin-deficient primary human tracheobronchial epithelial (HTBE) cells generated using the CRISPR-Cas9 system were stimulated with IL-13. To determine the function of Parkin, Parkin knockout (PKO) and wild-type (WT) mice were treated with IL-13 or allergen (house dust mite, HDM) in the presence or absence of mtDNA isolated from normal mouse lungs.

Results: Parkin mRNA expression in asthmatic airway epithelium was upregulated, which positively correlated with the levels of released mtDNA in BALF. IL-13-stimulated HTBE cells increased Parkin expression. Moreover, IL-13 induced mtDNA release in Parkin-sufficient, but not in Parkin-deficient HTBE cells. PKO (vs WT) mice attenuated airway mtDNA release and inflammation following IL-13 or HDM treatments. mtDNA amplified airway inflammation in mice treated with IL-13 or HDM. Notably, Parkin also mediated mtDNA-induced exacerbation of airway inflammation.

Conclusion: Our research findings suggest that Parkin promotes mtDNA release and inflammation in airways, thus improving our understanding of the complex role of Parkin and mitochondrial dysfunction in asthma pathogenesis.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214158DOI Listing
September 2020

Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover.

Sci Rep 2020 05 19;10(1):8284. Epub 2020 May 19.

Cedars Sinai Medical Center, Smidt Heart Institute, Los Angeles, USA.

Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy-specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) - in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.
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http://dx.doi.org/10.1038/s41598-020-64924-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237417PMC
May 2020

Minimal Invasive Pericardial Perfusion Model in Swine: A Translational Model for Cardiac Remodeling After Ischemia/Reperfusion Injury.

Front Physiol 2020 22;11:346. Epub 2020 Apr 22.

Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA, United States.

Rationale: Adverse remodeling leads to heart failure after myocardial infarction (MI), with important impact on morbidity and mortality. New therapeutic approaches are needed to further improve and broaden heart failure therapy. We established a minimally invasive, reproducible pericardial irrigation model in swine, as a translational model to study the impact of temperature on adverse cardiac remodeling and its molecular mechanisms after MI.

Objective: Chronic heart failure remains a leading cause of death in western industrialized countries, with a tremendous economic impact on the health care system. Previously, many studies have investigated mechanisms to reduce infarct size after ischemia/reperfusion injury, including therapeutic hypothermia. Nonetheless, the molecular mechanisms of adverse remodeling after MI remain poorly understood. By deciphering the latter, new therapeutic strategies can be developed to not only reduce rehospitalization of heart failure patients but also reduce or prevent adverse remodeling in the first place.

Methods And Results: After 90 min of MI, a 12Fr dual lumen dialysis catheter was place into the pericardium via minimal invasive, sub-xiphoidal percutaneous puncture. We performed pericardial irrigation with cold or warm saline for 60 min in 25 female farm pigs after ischemia and reperfusion. After one week of survival the heart was harvested for further studies. After cold pericardial irrigation we observed a significant decrease of systemic body temperature measured with a rectal probe in the cold group, reflecting that the heart was chilled throughout its entire thickness. The temperature remained stable in the control group during the procedure. We did not see any difference in arrhythmia or hemodynamic stability between both groups.

Conclusion: We established a minimally invasive, reproducible and translational model of pericardial irrigation in swine. This method enables the investigation of mechanisms involved in myocardial adverse remodeling after ischemia/reperfusion injury in the future.
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http://dx.doi.org/10.3389/fphys.2020.00346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188781PMC
April 2020

MitoPlex: A targeted multiple reaction monitoring assay for quantification of a curated set of mitochondrial proteins.

J Mol Cell Cardiol 2020 05 29;142:1-13. Epub 2020 Mar 29.

Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America. Electronic address:

Mitochondria are the major source of cellular energy (ATP), as well as critical mediators of widespread functions such as cellular redox balance, apoptosis, and metabolic flux. The organelles play an especially important role in the maintenance of cardiac homeostasis; their inability to generate ATP following impairment due to ischemic damage has been directly linked to organ failure. Methods to quantify mitochondrial content are limited to low throughput immunoassays, measurement of mitochondrial DNA, or relative quantification by untargeted mass spectrometry. Here, we present a high throughput, reproducible and quantitative mass spectrometry multiple reaction monitoring based assay of 37 proteins critical to central carbon chain metabolism and overall mitochondrial function termed 'MitoPlex'. We coupled this protein multiplex with a parallel analysis of the central carbon chain metabolites (219 metabolite assay) extracted in tandem from the same sample, be it cells or tissue. In tests of its biological applicability in cells and tissues, "MitoPlex plus metabolites" indicated profound effects of HMG-CoA Reductase inhibition (e.g., statin treatment) on mitochondria of i) differentiating C2C12 skeletal myoblasts, as well as a clear opposite trend of statins to promote mitochondrial protein expression and metabolism in heart and liver, while suppressing mitochondrial protein and ii) aspects of metabolism in the skeletal muscle obtained from C57Bl6 mice. Our results not only reveal new insights into the metabolic effect of statins in skeletal muscle, but present a new high throughput, reliable MS-based tool to study mitochondrial dynamics in both cell culture and in vivo models.
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http://dx.doi.org/10.1016/j.yjmcc.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347090PMC
May 2020

β -adrenoceptor activation improves skeletal muscle autophagy in neurogenic myopathy.

FASEB J 2020 04 28;34(4):5628-5641. Epub 2020 Feb 28.

Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

β -adrenoceptor agonists improve autophagy and re-establish proteostasis in cardiac cells; therefore, suggesting autophagy as a downstream effector of β -adrenoceptor signaling pathway. Here, we used the pharmacological and genetic tools to determine the autophagy effect of sustained β -adrenoceptor activation in rodents with neurogenic myopathy, which display impaired skeletal muscle autophagic flux. Sustained β -adrenoceptor activation using Formoterol (10 μg kg  day ), starting at the onset of neurogenic myopathy, prevents disruption of autophagic flux in skeletal muscle 14 days after sciatic nerve constriction. These changes are followed by reduction of the cytotoxic protein levels and increased skeletal muscle cross-sectional area and contractility properties. Of interest, sustained administration of Formoterol at lower concentration (1 μg kg  day ) induces similar improvements in skeletal muscle autophagic flux and contractility properties in neurogenic myopathy, without affecting the cross-sectional area. Sustained pharmacological inhibition of autophagy using Chloroquine (50 mg kg  day ) abolishes the beneficial effects of β -adrenoceptor activation on the skeletal muscle proteostasis and contractility properties in neurogenic myopathy. Further supporting an autophagy mechanism for β -adrenoceptor activation, skeletal muscle-specific deletion of ATG7 blunts the beneficial effects of β -adrenoceptor on skeletal muscle proteostasis and contractility properties in neurogenic myopathy in mice. These findings suggest autophagy as a critical downstream effector of β -adrenoceptor signaling pathway in skeletal muscle.
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http://dx.doi.org/10.1096/fj.201902305RDOI Listing
April 2020

Decrease of Cardiac Parkin Protein in Obese Mice.

Front Cardiovasc Med 2019 20;6:191. Epub 2020 Jan 20.

Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA, United States.

Mitophagy plays a major role in heart physiology. Impairment of Parkin-dependent mitophagy in heart is known to be deleterious. Obesity is a known cardiovascular risk factor. Impaired autophagy has been reported in models of obesity or hyperlipidemia/hypercholesterolemia; however less is known regarding obesity and mitophagy. The aim of this study was to evaluate the regulation of Parkin expression in hearts of mice fed a high fat diet. Interestingly, we found a significant decrease in Parkin protein in hearts of HFD mice compared those fed a low-fat diet. This was associated with mitochondrial dysfunction in the context of ischemia/reperfusion (I/R). This downregulation was not associated with a decrease in Parkin mRNA expression. We did not detect any change in the degradation rate of Parkin and only a slight decrease in its translation. The reduction of Parkin protein abundance in HFD hearts remains a mystery and will need further studies. However, Parkin depletion in the setting of obesity may contribute to cardiovascular risk.
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http://dx.doi.org/10.3389/fcvm.2019.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984192PMC
January 2020

Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure—A Report from the 2018 National Heart, Lung, and Blood Institute Workshop

Circulation 2019 10;140(14):1205-1216

Department of Genetic Medicine, The Johns Hopkins University, Baltimore, MD.

Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure, and other cardiovascular diseases, as well, but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute convened a group of leading experts in heart failure, cardiovascular diseases, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational, and clinical research focusing on the potential of mitochondria-based therapeutic strategies in heart failure. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of heart failure and cardiovascular diseases by using mitochondria-based approaches.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880654PMC
October 2019

Pushing the Heart Over a KLF(15).

J Am Coll Cardiol 2019 10;74(14):1820-1822

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine, Cedars-Sinai Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California.

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http://dx.doi.org/10.1016/j.jacc.2019.08.021DOI Listing
October 2019

Matrix-guided control of mitochondrial function in cardiac myocytes.

Acta Biomater 2019 10 8;97:281-295. Epub 2019 Aug 8.

Laboratory for Living Systems Engineering, Department of Biomedical Engineering, USC Viterbi School of Engineering, University of Southern California, Los Angeles CA, 90089, United States; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles CA, 90033, United States. Electronic address:

In ventricular myocardium, extracellular matrix (ECM) remodeling is a hallmark of physiological and pathological growth, coincident with metabolic rewiring of cardiac myocytes. However, the direct impact of the biochemical and mechanical properties of the ECM on the metabolic function of cardiac myocytes is mostly unknown. Furthermore, understanding the impact of distinct biomaterials on cardiac myocyte metabolism is critical for engineering physiologically-relevant models of healthy and diseased myocardium. For these reasons, we systematically measured morphological and metabolic responses of neonatal rat ventricular myocytes cultured on fibronectin- or gelatin-coated polydimethylsiloxane (PDMS) of three elastic moduli and gelatin hydrogels with four elastic moduli. On all substrates, total protein content, cell morphology, and the ratio of mitochondrial DNA to nuclear DNA were preserved. Cytotoxicity was low on all substrates, although slightly higher on PDMS compared to gelatin hydrogels. We also quantified oxygen consumption rates and extracellular acidification rates using a Seahorse extracellular flux analyzer. Our data indicate that several metrics associated with baseline glycolysis and baseline and maximum mitochondrial function are enhanced when cardiac myocytes are cultured on gelatin hydrogels compared to all PDMS substrates, irrespective of substrate rigidity. These results yield new insights into how mechanical and biochemical cues provided by the ECM impact mitochondrial function in cardiac myocytes. STATEMENT OF SIGNIFICANCE: Cardiac development and disease are associated with remodeling of the extracellular matrix coincident with metabolic rewiring of cardiac myocytes. However, little is known about the direct impact of the biochemical and mechanical properties of the extracellular matrix on the metabolic function of cardiac myocytes. In this study, oxygen consumption rates were measured in neonatal rat ventricular myocytes maintained on several commonly-used biomaterial substrates to reveal new relationships between the extracellular matrix and cardiac myocyte metabolism. Several mitochondrial parameters were enhanced on gelatin hydrogels compared to synthetic PDMS substrates. These data are important for comprehensively understanding matrix-regulation of cardiac myocyte physiology. Additionally, these data should be considered when selecting scaffolds for engineering in vitro cardiac tissue models.
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http://dx.doi.org/10.1016/j.actbio.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801042PMC
October 2019

Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis.

Biochim Biophys Acta Mol Basis Dis 2019 11 6;1865(11):165530. Epub 2019 Aug 6.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Background: During pancreatitis, autophagy is activated, but lysosomal degradation of dysfunctional organelles including mitochondria is impaired, resulting in acinar cell death. Retrospective cohort analyses demonstrated an association between simvastatin use and decreased acute pancreatitis incidence.

Methods: We examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20 mg/kg) for 24 h followed by 7 hourly cerulein injections and sacrificed 1 h after last injection to harvest blood and tissue for analysis.

Results: Pancreatic histopathology revealed that simvastatin reduced necrotic cell death, inflammatory cell infiltration and edema. We found that cerulein triggered mitophagy with autophagosome formation in acinar cells. However, autophagosome-lysosome fusion was impaired due to altered levels of LAMP-1, AMPK and ULK-1, resulting in autophagosome accumulation (incomplete autophagy). Simvastatin abrogated these effects by upregulating LAMP-1 and activating AMPK which phosphorylated ULK-1, resulting in increased formation of functional autolysosomes. In contrast, autophagosomes accumulated in control group during pancreatitis. The effects of simvastatin to promote autophagic flux were inhibited by chloroquine. Mitochondria from simvastatin-treated mice were resistant to calcium overload compared to control, suggesting that simvastatin induced mitochondrial quality control to eliminate susceptible mitochondria. Clinical specimens showed a significant increase in cell-free mtDNA in plasma during pancreatitis compared to normal controls. Furthermore, genetic deletion of parkin abrogated the benefits of simvastatin.

Conclusion: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.
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http://dx.doi.org/10.1016/j.bbadis.2019.08.006DOI Listing
November 2019

Myocardial hypothermia increases autophagic flux, mitochondrial mass and myocardial function after ischemia-reperfusion injury.

Sci Rep 2019 07 10;9(1):10001. Epub 2019 Jul 10.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Animal studies have demonstrated beneficial effects of therapeutic hypothermia on myocardial function, yet exact mechanisms remain unclear. Impaired autophagy leads to heart failure and mitophagy is important for mitigating ischemia/reperfusion injury. This study aims to investigate whether the beneficial effects of therapeutic hypothermia are due to preserved autophagy and mitophagy. Under general anesthesia, the left anterior descending coronary artery of 19 female farm pigs was occluded for 90 minutes with consecutive reperfusion. 30 minutes after reperfusion, we performed pericardial irrigation with warm or cold saline for 60 minutes. Myocardial tissue analysis was performed one and four weeks after infarction. Therapeutic hypothermia induced a significant increase in autophagic flux, mitophagy, mitochondrial mass and function in the myocardium after infarction. Cell stress, apoptosis, inflammation as well as fibrosis were reduced, with significant preservation of systolic and diastolic function four weeks post infarction. We found similar biochemical changes in human samples undergoing open chest surgery under hypothermic conditions when compared to the warm. These results suggest that autophagic flux and mitophagy are important mechanisms implicated in cardiomyocyte recovery after myocardial infarction under hypothermic conditions. New therapeutic strategies targeting these pathways directly could lead to improvements in prevention of heart failure.
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http://dx.doi.org/10.1038/s41598-019-46452-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620356PMC
July 2019

Murine macrophage autophagy protects against alcohol-induced liver injury by degrading interferon regulatory factor 1 (IRF1) and removing damaged mitochondria.

J Biol Chem 2019 08 24;294(33):12359-12369. Epub 2019 Jun 24.

Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048. Electronic address:

Excessive alcohol consumption induces intestinal dysbiosis of the gut microbiome and reduces gut epithelial integrity. This often leads to portal circulation-mediated translocation of gut-derived microbial products, such as lipopolysaccharide (LPS), to the liver, where these products engage Toll-like receptor 4 (TLR4) and initiate hepatic inflammation, which promotes alcoholic liver disease (ALD). Although the key self-destructive process of autophagy has been well-studied in hepatocytes, its role in macrophages during ALD pathogenesis remains elusive. Using WT and myeloid cell-specific () knockout ( ) mice, we found that chronic ethanol feeding for 6 weeks plus LPS injection enhances serum alanine aminotransferase and IL-1β levels and augments hepatic C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) expression in WT mice, a phenotype that was further exacerbated in mice. macrophages exhibited defective mitochondrial respiration and displayed elevated mitochondrial reactive oxygen species production and inflammasome activation relative to WT cells. Interestingly, compared with WT cells, macrophages also had a drastically increased abundance and nuclear translocation of interferon regulatory factor 1 (IRF1) after LPS stimulation. Mechanistically, LPS induced co-localization of IRF1 with the autophagy adaptor p62 and the autophagosome, resulting in subsequent IRF1 degradation. However, upon p62 silencing or Atg7 deletion, IRF1 started to accumulate in autophagy-deficient macrophages and translocated into the nucleus, where it induced CCL5 and CXCL10 expression. In conclusion, macrophage autophagy protects against ALD by promoting IRF1 degradation and removal of damaged mitochondria, limiting macrophage activation and inflammation.
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http://dx.doi.org/10.1074/jbc.RA119.007409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699832PMC
August 2019

Suppression of Cardiac Autophagy by Hyperinsulinemia in Insulin Receptor-Deficient Hearts Is Mediated by Insulin-Like Growth Factor Receptor Signaling.

Antioxid Redox Signal 2019 08 20;31(6):444-457. Epub 2019 Jun 20.

1 Department of Nutrition and Integrative Physiology, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah.

Autophagy is a catabolic process required for the maintenance of cardiac health. Insulin and insulin-like growth factor 1 (IGF-1) are potent inhibitors of autophagy and as such, one would predict that autophagy will be increased in the insulin-resistant/diabetic heart. However, autophagy is rather decreased in the hearts of diabetic/insulin-resistant mice. The aim of this study is to determine the contribution of IGF-1 receptor signaling to autophagy suppression in insulin receptor (IR)-deficient hearts. Absence of IRs in the heart was associated with reduced autophagic flux, and further inhibition of autophagosome clearance reduced survival, impaired contractile function, and enhanced myocyte loss. Contrary to the setting, isolated cardiomyocytes from IR-deficient hearts exhibited unrestrained autophagy in the absence of insulin, whereas addition of insulin was able to suppress autophagy. To investigate the mechanisms involved in the maintenance of the responsiveness to insulin in IR-deficient hearts, we generated mice lacking both IRs and one copy of the IGF-1 receptor (IGF-1R) in cardiac cells and showed that these mice had increased autophagy. This study unveils a new mechanism by which IR-deficient hearts can still respond to insulin to suppress autophagy, in part, through activation of IGF-1R signaling. This is a highly significant observation because it is the first to show that systemic hyperinsulinemia can suppress autophagy in IR-deficient hearts through IGF-1R signaling.
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http://dx.doi.org/10.1089/ars.2018.7640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653796PMC
August 2019

Methionine Adenosyltransferase α1 Is Targeted to the Mitochondrial Matrix and Interacts with Cytochrome P450 2E1 to Lower Its Expression.

Hepatology 2019 12 25;70(6):2018-2034. Epub 2019 Jun 25.

Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA.

Methionine adenosyltransferase α1 (MATα1, encoded by MAT1A) is responsible for hepatic biosynthesis of S-adenosyl methionine, the principal methyl donor. MATα1 also act as a transcriptional cofactor by interacting and influencing the activity of several transcription factors. Mat1a knockout (KO) mice have increased levels of cytochrome P450 2E1 (CYP2E1), but the underlying mechanisms are unknown. The aims of the current study were to identify binding partners of MATα1 and elucidate how MATα1 regulates CYP2E1 expression. We identified binding partners of MATα1 by coimmunoprecipitation (co-IP) and mass spectrometry. Interacting proteins were confirmed using co-IP using recombinant proteins, liver lysates, and mitochondria. Alcoholic liver disease (ALD) samples were used to confirm relevance of our findings. We found that MATα1 negatively regulates CYP2E1 at mRNA and protein levels, with the latter being the dominant mechanism. MATα1 interacts with many proteins but with a predominance of mitochondrial proteins including CYP2E1. We found that MATα1 is present in the mitochondrial matrix of hepatocytes using immunogold electron microscopy. Mat1a KO hepatocytes had reduced mitochondrial membrane potential and higher mitochondrial reactive oxygen species, both of which were normalized when MAT1A was overexpressed. In addition, KO hepatocytes were sensitized to ethanol and tumor necrosis factor α-induced mitochondrial dysfunction. Interaction of MATα1 with CYP2E1 was direct, and this facilitated CYP2E1 methylation at R379, leading to its degradation through the proteasomal pathway. Mat1a KO livers have a reduced methylated/total CYP2E1 ratio. MATα1's influence on mitochondrial function is largely mediated by its effect on CYP2E1 expression. Patients with ALD have reduced MATα1 levels and a decrease in methylated/total CYP2E1 ratio. Conclusion: Our findings highlight a critical role of MATα1 in regulating mitochondrial function by suppressing CYP2E1 expression at multiple levels.
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http://dx.doi.org/10.1002/hep.30762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842664PMC
December 2019

Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis.

J Am Coll Cardiol 2019 03;73(10):1149-1169

Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; National Nanotechnology Center, Bilkent University, Ankara, Turkey; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma.

Objectives: Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis.

Methods: The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes.

Results: The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis.

Conclusions: These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.
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http://dx.doi.org/10.1016/j.jacc.2018.12.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424590PMC
March 2019

Autophagy plays a protective role against Trypanosoma cruzi infection in mice.

Virulence 2019 12;10(1):151-165

a Laboratorio de Biología de Trypanosoma cruzi y la célula hospedadora- Instituto de Histología y Embriología "Dr. Mario H. Burgos" , (IHEM-CONICET- Universidad Nacional de Cuyo) , Mendoza , Argentina.

Autophagy is a catabolic pathway required for cellular and organism homeostasis. Autophagy participates in the innate and adaptive immune responses at different levels. Xenophagy is a class of selective autophagy that involves the elimination of intracellular pathogens. Trypanosoma cruzi is the causative agent of Chagas, a disease that affects 8 million individuals worldwide. Previously, our group has demonstrated that autophagy participates in the invasion of T. cruzi in non-phagocytic cells. In this work we have studied the involvement of autophagy in the development of T. cruzi infection in mice. Beclin-1 is a protein essential for autophagy, required for autophagosome biogenesis and maturation. We have performed an acute model of infection on the autophagic deficient Beclin-1 heterozygous knock-out mice (Bcln) and compared to control Bcln animals. In addition, we have analyzed the infection process in both peritoneal cells and RAW macrophages. Our results have shown that the infection was more aggressive in the autophagy-deficient mice, which displayed higher numbers of parasitemia, heart´s parasitic nests and mortality rates. We have also found that peritoneal cells derived from Bcln animals and RAW macrophages treated with autophagy inhibitors displayed higher levels of infection compared to controls. Interestingly, free cytosolic parasites recruited LC3 protein and other markers of xenophagy in control compared to autophagy-deficient cells. Taken together, these data suggest that autophagy plays a protective role against T. cruzi infection in mice, xenophagy being one of the processes activated as part of the repertoire of immune responses generated by the host.
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http://dx.doi.org/10.1080/21505594.2019.1584027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550547PMC
December 2019

Myocardial fibrosis after adrenergic stimulation as a long-term sequela in a mouse model of Kawasaki disease vasculitis.

JCI Insight 2019 Feb 7;4(3). Epub 2019 Feb 7.

Departments of Biomedical Sciences and Pediatrics, Divisions of Infectious Diseases and Immunology.

Kawasaki disease (KD), the leading cause of acquired cardiac disease among children, is often associated with myocarditis that may lead to long-term myocardial dysfunction and fibrosis. Although those myocardial changes develop during the acute phase, they may persist for decades and closely correlate with long-term myocardial sequelae. Using the Lactobacillus casei cell wall extract-induced (LCWE-induced) KD vasculitis murine model, we investigated long-term cardiovascular sequelae, such as myocardial dysfunction, fibrosis, and coronary microvascular lesions following adrenergic stimuli after established KD vasculitis. We found that adrenergic stimulation with isoproterenol following LCWE-induced KD vasculitis in mice was associated with increased risk of cardiac hypertrophy and myocardial fibrosis, diminished ejection fraction, and increased serum levels of brain natriuretic peptide. Myocardial fibrosis resulting from pharmacologic-induced exercise after KD development was IL-1 signaling dependent and was associated with a significant reduction in myocardial capillary CD31 expression, indicative of a rarefied myocardial capillary bed. These observations suggest that adrenergic stimulation after KD vasculitis may lead to cardiac hypertrophy and bridging fibrosis in the myocardium in the LCWE-induced KD vasculitis mouse model and that this process involves IL-1 signaling and diminished microvascular circulation in the myocardium.
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http://dx.doi.org/10.1172/jci.insight.126279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413776PMC
February 2019

Retraction Note: Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell derivatives.

Nat Commun 2019 Feb 2;10(1):645. Epub 2019 Feb 2.

Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

This paper has been retracted at the request of the authors.
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http://dx.doi.org/10.1038/s41467-019-08572-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359997PMC
February 2019

Coxsackievirus B infection induces the extracellular release of miR-590-5p, a proviral microRNA.

Virology 2019 03 30;529:169-176. Epub 2019 Jan 30.

The Smidt Heart Institute and the Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States. Electronic address:

Coxsackievirus B is a significant human pathogen and is a leading cause of myocarditis. We and others have observed that certain enteroviruses including coxsackievirus B cause infected cells to shed extracellular vesicles containing infectious virus. Recent reports have shown that vesicle-bound virus can infect more efficiently than free virus. Though microRNAs are differentially regulated in cells following infection, few have been associated with the vesicles shed from infected cells. Here we report exclusive trafficking of specific microRNAs into viral vesicles compared to vesicles from non-infected cells. We found that the most highly-expressed unique microRNA in viral vesicles was miR-590-5p, which facilitates prolonged viral replication by blocking apoptotic factors. Cells over-expressing this miR were significantly more susceptible to infection. This may be a mechanism by which coxsackievirus B boosts subsequent rounds of infection by co-packaging virus and a select set of pro-viral microRNAs in extracellular vesicles.
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http://dx.doi.org/10.1016/j.virol.2019.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382511PMC
March 2019

Oxidative muscles have better mitochondrial homeostasis than glycolytic muscles throughout life and maintain mitochondrial function during aging.

Aging (Albany NY) 2018 11;10(11):3327-3352

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Preservation of mitochondrial function, which is dependent on mitochondrial homeostasis (biogenesis, dynamics, disposal/recycling), is critical for maintenance of skeletal muscle function. Skeletal muscle performance declines upon aging (sarcopenia) and is accompanied by decreased mitochondrial function in fast-glycolytic muscles. Oxidative metabolism promotes mitochondrial homeostasis, so we investigated whether mitochondrial function is preserved in oxidative muscles. We compared tibialis anterior (predominantly glycolytic) and soleus (oxidative) muscles from young (3 mo) and old (28-29 mo) C57BL/6J mice. Throughout life, the soleus remained more oxidative than the tibialis anterior and expressed higher levels of markers of mitochondrial biogenesis, fission/fusion and autophagy. The respiratory capacity of mitochondria isolated from the tibialis anterior, but not the soleus, declined upon aging. The soleus and tibialis anterior exhibited similar aging-associated changes in mitochondrial biogenesis, fission/fusion, disposal and autophagy marker expression, but opposite changes in fiber composition: the most oxidative fibers declined in the tibialis anterior, while the more glycolytic fibers declined in the soleus. In conclusion, oxidative muscles are protected from mitochondrial aging, probably due to better mitochondrial homeostasis and aging-associated changes in fiber composition. Exercise training aimed at enriching oxidative fibers may be valuable in preventing mitochondria-related aging and its contribution to sarcopenia.
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http://dx.doi.org/10.18632/aging.101643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286850PMC
November 2018
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