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Atherosclerosis Regression and Cholesterol Efflux in Hypertriglyceridemic Mice

Josefs, Tatjana; Basu, Debapriya; Vaisar, Tomas; Arets, Britt; Kanter, Jenny E; Huggins, Lesley-Ann; Hu, Yunying; Liu, Jianhua; Clouet-Foraison, Noemie; Heinecke, Jay W; Bornfeldt, Karin E; Goldberg, Ira J; Fisher, Edward A
[Figure: see text].
PMCID:7979499
PMID: 33530703
ISSN: 1524-4571
CID: 4850882

Cardiomyocyte Krüppel-Like Factor 5 Promotes De Novo Ceramide Biosynthesis and Contributes to Eccentric Remodeling in Ischemic Cardiomyopathy

Hoffman, Matthew; Palioura, Dimitra; Kyriazis, Ioannis D; Cimini, Maria; Badolia, Rachit; Rajan, Sudarsan; Gao, Erhe; Nikolaidis, Nikolas; Schulze, P Christian; Goldberg, Ira J; Kishore, Raj; Yang, Vincent W; Bannister, Thomas D; Bialkowska, Agnieszka B; Selzman, Craig H; Drakos, Stavros G; Drosatos, Konstantinos
BACKGROUND:We previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure. METHODS:). We identified the involvement of KLF5 in regulating lipid metabolism and ceramide accumulation after MI using liquid chromatography-tandem mass spectrometry, and Western blot and real-time polymerase chain reaction analysis of ceramide metabolism-related genes. We lastly evaluated the effect of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA [reverse tetracycline-controlled transactivator]-KLF5) on cardiac function and ceramide metabolism, and rescued the phenotype using myriocin to inhibit ceramide biosynthesis. RESULTS:mice was not different in control mice. KLF5 ablation suppressed the expression of SPTLC1 and SPTLC2 (serine palmitoyltransferase [SPT] long-chain base subunit ()1 2, respectively), which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are increased in heart failure patients. Consistently, αMHC-rtTA-KLF5 mice showed increased SPTLC1 and SPTLC2 expression, higher myocardial ceramide levels, and systolic dysfunction beginning 2 weeks after KLF5 induction. Treatment of αMHC-rtTA-KLF5 mice with myriocin that inhibits SPT, suppressed myocardial ceramide levels and alleviated systolic dysfunction. CONCLUSIONS:KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.
PMCID:7965352
PMID: 33430631
ISSN: 1524-4539
CID: 4849272

KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy

Kyriazis, Ioannis D; Hoffman, Matthew; Gaignebet, Lea; Lucchese, Anna Maria; Markopoulou, Eftychia; Palioura, Dimitra; Wang, Chao; Bannister, Thomas D; Christofidou-Solomidou, Melpo; Oka, Shin-Ichi; Sadoshima, Junichi; Koch, Walter J; Goldberg, Ira J; Yang, Vincent W; Bialkowska, Agnieszka B; Kararigas, Georgios; Drosatos, Konstantinos
RATIONALE/BACKGROUND:Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increased cardiac expression of KLF5 (Krüppel-like factor-5) and PPARα (peroxisome proliferator-activated receptor) that regulate cardiac lipid metabolism. OBJECTIVE:In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation. METHODS AND RESULTS/RESULTS:)4 promoter and induction of NOX4 (NADPH oxidase 4) expression. This was accompanied by accumulation of cardiac ceramides. Pharmacological or genetic KLF5 inhibition alleviated superoxide formation, prevented ceramide accumulation, and improved cardiac function in diabetic mice. CONCLUSIONS:Diabetes-mediated activation of cardiomyocyte FOXO1 increases KLF5 expression, which stimulates NOX4 expression, ceramide accumulation, and causes DbCM.
PMCID:7870005
PMID: 33539225
ISSN: 1524-4571
CID: 4799012

Myxedema Heart and Pseudotamponade

Baldwin, Chelsey; Newman, Jonathan D; Vallejo, Franco; Peck, Valerie; Greene, Loren Wissner; Goldberg, Ira J
Context/UNASSIGNED:Thyroid hormone plays a critical role in cardiovascular function. Severe hypothyroidism can be associated with "myxedema heart" characterized by relative bradycardia and pericardial effusion. Effusions associated with severe hypothyroidism can be large. Despite the large volume of effusions, tamponade is not a common consequence. However, with the incorporation of echocardiography into routine practice for evaluation of effusion, echocardiographic findings suggestive of clinical tamponade occur frequently. Case Description/UNASSIGNED:We report a series of 3 patients with large pericardial effusions secondary to severe hypothyroidism. These cases serve to demonstrate the discordance between echocardiographic signs consistent with tamponade with a patient's stable clinical hemodynamics. We also report the development of bronchial obstruction, a rare complication of a large effusion due to severe hypothyroidism. Conclusions/UNASSIGNED:While pericardial effusion associated with severe hypothyroidism has been described for decades, the echocardiographic findings may be less well known and may lead to unnecessary downstream testing or invasive management. We use our case series to facilitate a summary of what is known about the epidemiology, mechanism and physiology, and expected outcomes of myxedema associated pericardial effusion. Finally, in the setting of current paucity of clinical guidelines, we aim to familiarize clinicians with the phenomenon of pseudotamponade and suggest management strategies for myxedema associated pericardial effusion to guide clinicians to use conservative medical management in majority of cases.
PMCID:7737394
PMID: 33354637
ISSN: 2472-1972
CID: 4799432

Ketogenic diets, not for everyone

Goldberg, Ira J; Ibrahim, Nouran; Bredefeld, Cindy; Foo, Sandra; Lim, Vivien; Gutman, Deborah; Huggins, Lesley-Ann; Hegele, Robert A
BACKGROUND:The adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. OBJECTIVE:The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. METHODS:We describe 5 patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well-described underlying genetic hyperlipidemia. RESULTS:Three out of 5 patients had extraordinary increases of blood cholesterol levels to over 500 mg/dL. The other 2 patients more than doubled their low-density lipoprotein cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in 2 patients, with no major mutations found. No potential genetic cause was seen in a fourth patient, and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory low-density lipoprotein cholesterol reduction on ezetimibe. CONCLUSION/CONCLUSIONS:These cases should serve as a caution that high-fat low-carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.
PMID: 33191194
ISSN: 1933-2874
CID: 4716282

A Case Report: Euglycemic Diabetic Ketoacidosis Presenting as Chest Pain in a Patient on a Low Carbohydrate Diet [Case Report]

Dorcely, Brenda; Nitis, Juliana; Schwartzbard, Arthur; Newman, Jonathan; Goldberg, Ira; Sum, Melissa
INTRODUCTION/BACKGROUND:Sodium-glucose cotransporter-2 [SGLT2] inhibitors reduce cardiovascular events and mortality in patients with diabetes, particularly patients with established cardiovascular disease. Euglycemic diabetic ketoacidosis [euDKA], a complication of SGLT2 therapy, can be exacerbated by a low carbohydrate diet. CASE REPORT/METHODS:A 61-year-old man with a history of type 2 diabetes, taking a SGLT2 inhibitor empagliflozin 10 mg orally daily, presented to the emergency room with a 2-day history of nausea and chest pain. A week prior to presentation, he had started a ketogenic diet. He was initially admitted with a diagnosis of acute coronary syndrome. On initial assessment in the emergency room, his cardiac enzymes were normal and there were no ischemic changes in his ECG. As there was concern for unstable angina, he underwent cardiac catheterization, which showed a known total occlusion with collaterals and arteries with non-obstructive disease without evidence of acute plaque rupture. His baseline laboratory assessments revealed an elevated anion gap of 17, increased urinary and plasma ketones, and metabolic acidosis. His plasma glucose level was 84 mg/dL. The diagnosis of euDKA was made, and treatment with intravenous fluids and insulin was initiated. His chest pain and nausea subsequently resolved. CONCLUSION/CONCLUSIONS:We present a case of euDKA triggered by a ketogenic diet while on SGLT2 inhibitor therapy presenting as chest pain. The recognition of euDKA is important in the context of increased SGLT2 use for management of cardiovascular risk for patients with diabetes.
PMID: 32178617
ISSN: 1875-6417
CID: 4353492

Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline

Newman, Connie B; Blaha, Michael J; Boord, Jeffrey B; Cariou, Bertrand; Chait, Alan; Fein, Henry G; Ginsberg, Henry N; Goldberg, Ira J; Murad, M Hassan; Subramanian, Savitha; Tannock, Lisa R
OBJECTIVE:This guideline will provide the practicing endocrinologist with an approach to the assessment and treatment of dyslipidemia in patients with endocrine diseases, with the objective of preventing cardiovascular (CV) events and triglyceride-induced pancreatitis. The guideline reviews data on dyslipidemia and atherosclerotic cardiovascular disease (ASCVD) risk in patients with endocrine disorders and discusses the evidence for the correction of dyslipidemia by treatment of the endocrine disease. The guideline also addresses whether treatment of the endocrine disease reduces ASCVD risk. CONCLUSION/CONCLUSIONS:This guideline focuses on lipid and lipoprotein abnormalities associated with endocrine diseases, including diabetes mellitus, and whether treatment of the endocrine disorder improves not only the lipid abnormalities, but also CV outcomes. Based on the available evidence, recommendations are made for the assessment and management of dyslipidemia in patients with endocrine diseases.
PMID: 32951056
ISSN: 1945-7197
CID: 4735422

Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis

Flynn, Michelle C; Kraakman, Michael J; Tikellis, Christos; Lee, Man Ks; Hanssen, Nordin Mj; Kammoun, Helene L; Pickering, Raelene; Dragoljevic, Dragana; Al-Sharea, Annas; Barrett, Tessa J; Hortle, Fiona; Byrne, Frances L; Olzomer, Ellen; McCarthy, Domenica A; Schalkwijk, Casper G; Forbes, Josephine M; Hoehn, Kyle; Makowski, Liza; Lancaster, Graeme I; El-Osta, Assam; Fisher, Edward A; Goldberg, Ira J; Cooper, Mark E; Nagareddy, Prabhakara R; Thomas, Merlin C; Murphy, Andrew J
Rationale: Treatment efficacy for diabetes is largely determined by assessment of HbA1c levels, which poorly reflects direct glucose variation. People with pre-diabetes and diabetes spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH) appear to be an independent risk-factor for cardiovascular disease (CVD) but the pathological basis for this association is unclear. Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. Methods and Results: To create a mouse model of TIH we administered 4 bolus doses of glucose at 2hr intervals intraperitoneally once to wild-type (WT) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8 or its cognate receptor Rage, prevented monocytosis. Mechanistically, glucose uptake via GLUT-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to CVD. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE axis could represent a viable approach to protect the vulnerable blood vessels in diabetes.
PMID: 32564710
ISSN: 1524-4571
CID: 4514372

Regulation of lipoprotein lipase-mediated lipolysis of triglycerides

Basu, Debapriya; Goldberg, Ira J
PURPOSE OF REVIEW/OBJECTIVE:To discuss the recent developments in structure, function and physiology of lipoprotein lipase (LpL) and the regulators of LpL, which are being targeted for therapy. RECENT FINDINGS/RESULTS:Recent studies have revealed the long elusive crystal structure of LpL and its interaction with glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1). New light has been shed on LpL being active as a monomer, which brings into questions previous thinking that LpL inhibitors like angiopoietin-like 4 (ANGPTL4) and stabilizers like LMF1 work on disrupting or maintaining LpL in dimer form. There is increasing pharmaceutical interest in developing targets to block LpL inhibitors like ANGPTL3. Other approaches to reducing circulating triglyceride levels have been using an apoC2 mimetic and reducing apoC3. SUMMARY/CONCLUSIONS:Lipolysis of triglyceride-rich lipoproteins by LpL is a central event in lipid metabolism, releasing fatty acids for uptake by tissues and generating low-density lipoprotein and expanding high-density lipoprotein. Recent mechanistic insights into the structure and function of LpL have added to our understanding of triglyceride metabolism. This has also led to heightened interest in targeting its posttranslational regulators, which can be the next generation of lipid-lowering agents used to prevent hypertriglyceridemic pancreatitis and, hopefully, cardiovascular disease.
PMID: 32332431
ISSN: 1473-6535
CID: 4464392

CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Wang, Haiping; Franco, Fabien; Tsui, Yao-Chen; Xie, Xin; Trefny, Marcel P; Zappasodi, Roberta; Mohmood, Syed Raza; Fernández-García, Juan; Tsai, Chin-Hsien; Schulze, Isabell; Picard, Florence; Meylan, Etienne; Silverstein, Roy; Goldberg, Ira; Fendt, Sarah-Maria; Wolchok, Jedd D; Merghoub, Taha; Jandus, Camilla; Zippelius, Alfred; Ho, Ping-Chih
Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
PMID: 32066953
ISSN: 1529-2916
CID: 4312102