Maayan Waldman

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CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1α Activation

Cardiovascular Pharmacology: Open Access, 2018

We have previously shown that an Epoxyeicosatrienoic Acid (EET)-agonist has pleiotropic effects a... more We have previously shown that an Epoxyeicosatrienoic Acid (EET)-agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC-1α, HO-1 levels, insulin receptor This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Silencing the Adipocytokine NOV: A Novel Approach to Reversing Oxidative Stress-Induced Cardiometabolic Dysfunction

Cells

Objective: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardi... more Objective: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. Methods: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the h...

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Caloric Restriction in Obesity and Diabetic Heart Disease

Personalized Nutrition as Medical Therapy for High-Risk Diseases, 2020

Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

Cellular Physiology and Biochemistry, 2015

Background/Aims: Ischemia/reperfusion (I/R) injury is the main cause of both primary graft dysfun... more Background/Aims: Ischemia/reperfusion (I/R) injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC), a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg) in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. Methods: C57Bl Mice were studied in in vivo model of hepatic segmental (70%) ischemia for 60min followed by reperfusion for 6 hours. Results: THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway), the acute proinflammatory resp...

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Autophagy guided interventions to modify the cardiac phenotype of Danon disease

Biochemical Pharmacology

Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion

Antioxidants

Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, y... more Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1α (transgenic-adipocyte-PGC-1α) at week 20, and continued on H.F.D. for weeks 20–28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1α and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial r...

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Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, obesity, and activation of the renin angiotensin system

Cardiovascular Diabetology

Background Diabetic and obese patients are at higher risk of severe disease and cardiac injury in... more Background Diabetic and obese patients are at higher risk of severe disease and cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin–angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice. Methods Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in ACE2 mRNA and protein expression in heart tissue and serum. ACE2 expression was compared with clinical risk factors: diabetes, obesity and di...

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$Research paper thumbnail of Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction$

Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction

Nature Communications

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure ... more Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein ...

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The Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1α–Heme Oxygenase 1 Axis, a Powerful Antioxidative Pathway with Potential to Attenuate Diabetic Cardiomyopathy

Antioxidants & Redox Signaling

Leptin modulates gene expression in the heart and cardiomyocytes towards mitigating ischemia-induced damage

Experimental Cell Research

Therapeutic approaches to diabetic cardiomyopathy: Targeting the antioxidant pathway

Prostaglandins & Other Lipid Mediators

The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy

International Journal of Molecular Sciences

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy... more Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the...

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PARP-1 inhibition protects the diabetic heart through activation of SIRT1-PGC-1α axis

Experimental Cell Research

Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models

Heart rhythm, Jul 1, 2017

The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused b... more The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency. The aims of this study were to develop a viral-delivered gene therapy for CPVT2 and to determine the relationship between CASQ2 expression and antiarrhythmic efficacy in a murine model. We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2(D307H)) or CASQ2 knockout (CASQ2(Δ/Δ)). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAVCASQ2) were injected into the heart or intraperitoneally to 12-week-old mice. A telemetry device was implanted, and mice underwent provocation testing 7-8 weeks after gene therapy. CASQ2(Δ/Δ) mice injected intracardiacally with AAVCASQ2 expressed 40% ± 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2(Δ/Δ) mice (n = 10; P < .05). Intraperitoneal therapy led to a significantly elevated expression of the CASQ2 pr...

Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving 'SIRT1 and PGC-1α

Cardiovascular diabetology, Jan 2, 2018

Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (DM2) are al... more Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (DM2) are all linked to diabetic cardiomyopathy that lead to heart failure. Cardiomyopathy is initially characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and fibrosis, both of which are aggravated by angiotensin. Caloric restriction (CR) is cardioprotective in animal models of heart disease through its catabolic activity and activation of the expression of adaptive genes. We hypothesized that in the diabetic heart; this effect involves antioxidant defenses and is mediated by SIRT1 and the transcriptional coactivator PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator). Obese Leptin resistant (db/db) mice characterized by DM2 were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly either on a CR diet or fed ad libitum. Cardiomyocytes were exposed to high levels of glucose and were treated with...

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Caloric restriction ameliorates cardiomyopathy in animal model of diabetes

Experimental Cell Research, 2017

The role of 20-HETE in cardiovascular diseases and its risk factors

Prostaglandins & Other Lipid Mediators, 2016

Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which is Required for HO-1 Expression and Increased Mitochondrial Function

Stem cells and development, Jan 25, 2016

Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate ... more Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered pre-adipocyte function, enhanced of peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression and increased mitochondrial function in the 3T3-L1 pre-adipocyte. Cells treated with EET resulted in an increase, p<0.05, in PGC-1α and a decrease in mitochondrial-derived ROS (MitoSox), p<0.05. The EET increase in HO-1 levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, p<0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial SOD in a PGC-1α -dependent manner, p<0.05. The increase in PGC-1α was associated with an increase in β-catenin, (p<0.05), adiponectin expression, p<0.05, and lipid accumulation, p<0.02. EET decreased heme levels and mi...

Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection

PLOS ONE, 2015

αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestor... more αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Purinergic Signalling, 2013

Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiolo... more Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y2 and P2Y4 (UTP-activated), P2Y6, and P2Y14. Previously, we showed that uridine 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-triphosphate (UTP) activating P2Y2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y2R in vitro and in vivo following MI using uridine-5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y2R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y2R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0 ± 3.1 % vs. 33.4 ± 2.7 %, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and c-Jun phosphorylation increased. Thus, P2Y2R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo.

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