Abstract 113: Targeting Receptor-interacting Protein 140 (RIP140) To Modulate Energy Metabolism In The Failing Heart

During the development of heart failure (HF), the PPAR/ERR complex becomes deactivated resulting in diminished capacity for mitochondrial fatty acid oxidation (FAO) and ATP production leading to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PPAR/ERR in some extra-cardiac tissues. We hypothesized that inhibition of RIP140 would re-activate PPAR/ERR enhancing capacity for fuel catabolism and ATP production in the failing heart. Heart and skeletal muscle-specific RIP140 knockout mice (strRIP140KO) were resistant to the development of cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload that mimicked features of HF with preserved ejection fraction (HFpEF). To further evaluate the role of RIP140 in heart, cardiac-specific (cs) RIP140KO mice were generated. 13 C-substrate NMR studies demonstrated that palmitate oxidation and triglyceride turnover rates were significantly accelerated in isolated perfused csRIP140KO hearts. csRIP140KO were subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), to produce HF with reduced EF (HFrEF). Compared to controls, csRIP140KO exhibited reduced left ventricular remodeling and systolic dysfunction when subjected to TAC/MI. RNA-sequence analysis demonstrated that many genes involved in FAO, branched-chain amino acid catabolism, oxidative phosphorylation, and adult muscle contraction programs were significantly “protected” (less downregulation) by RIP140 deletion in the context of TAC/MI. To identify candidate cardiac RIP140 targets, “CUT&RUN”-sequencing was conducted on cardiomyocytes (CM) from csRIP140KO and controls to identify changes in enhancer regions. Motif analysis of peaks with increased H3K27ac deposition in the csRIP140KO CM identified ERR, PPAR, myocyte enhancer 2 (MEF2), glucocorticoid receptor (GR), and kruppel-like factor (KLF) binding sites. We conclude that RIP140 serves as a global co-repressor of a network of transcription factors that control cardiac energy metabolic and contractile function, and that inhibition of RIP140 could prove to be a novel therapeutic approach for HF.

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Abstract 13921: Targeting Receptor-Interacting Protein 140 to Modulate Energy Metabolism in the Failing Heart

Circulation ◽

10.1161/circ.142.suppl_3.13921 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Tsunehisa Yamamoto ◽

Elizabeth Pruzinsky ◽

Kirill Batmanov ◽

Daniel P Kelly

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Systolic Function ◽

Systolic Dysfunction ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Interacting Protein ◽

Failing Heart ◽

Metabolic Genes ◽

Cardiac Energy

The nuclear receptors, peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and their co-regulator PPARγ coactivator-1α (PGC-1α), control postnatal cardiac mitochondrial biogenesis and energy metabolism. During the development of heart failure (HF), the activity of PGC-1/PPAR/ERR is reduced resulting in diminished capacity for fatty acid oxidation (FAO) and ATP production potentially contributing to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PGC-1/PPAR/ERR in skeletal muscle and adipose tissue. We hypothesized that RIP140 represses cardiac energy metabolism in the normal and failing heart. Accordingly, we targeted Nrip1 (encoding RIP140) using a muscle creatinine kinase (MCK)-driven Cre recombinase to generate striated muscle-specific RIP140 knockout (msRIP140 KO) mice. msRIP140 KO mice appeared normal at baseline with no difference in survival or cardiac systolic function compared to littermate controls. RNA-sequence analysis demonstrated that the expression of genes involved in a wide array of mitochondrial energy metabolic pathways including FAO, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and branched-chain amino acid (BCAA) degradation pathways were upregulated in msRIP140 KO ventricles, and in msRIP140 KO skeletal muscle. msRIP140 KO mice exhibited significantly less cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload. Next, cardiac-specific (cs) RIP140 KO mice were generated and subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), an established HF model. csRIP140 KO mice exhibited less cardiac remodeling and systolic dysfunction compared to littermate controls, along with less downregulation of metabolic genes and induction of cardiac stress ( Nppa and Nppb ) and fibrosis response markers ( Tgfb2 and Col3a1 ). We conclude that RIP140 serves as a global co-repressor of cardiac energy metabolic genes in the adult heart and that modulation of RIP140 activity could prove to be a novel therapeutic approach for HF.

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Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19

International Journal of Molecular Sciences ◽

10.3390/ijms23010045 ◽

2021 ◽

Vol 23 (1) ◽

pp. 45

Author(s):

Reinis Vilskersts ◽

Dana Kigitovica ◽

Stanislava Korzh ◽

Melita Videja ◽

Karlis Vilks ◽

...

Keyword(s):

Ventricular Dysfunction ◽

Systolic Dysfunction ◽

Cardiovascular Complications ◽

Experimental Models ◽

Left Ventricular ◽

Acid Oxidation ◽

Mitochondrial Bioenergetics ◽

Mitochondrial Fatty Acid Oxidation ◽

Lv Dysfunction ◽

Mitochondrial Fatty Acid

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.

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Faculty Opinions recommendation of Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089389.542618 ◽

2007 ◽

Author(s):

Jerome Fleg

Keyword(s):

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Systolic Dysfunction ◽

Left Ventricular

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Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00042.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. H244-H249 ◽

Cited By ~ 5

Author(s):

Nathan A. Trueblood ◽

Patrick R. Inscore ◽

Daniel Brenner ◽

Daniel Lugassy ◽

Carl S. Apstein ◽

...

Keyword(s):

Myocardial Infarction ◽

Exercise Capacity ◽

Time Course ◽

Ventricular Remodeling ◽

Contractile Function ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Early Recovery ◽

Functional Changes ◽

Lv Remodeling

After myocardial infarction (MI), there is progressive left ventricular (LV) remodeling and impaired exercise capacity. We tested the hypothesis that LV remodeling results in structural and functional changes that determine exercise impairment post-MI. Rats underwent coronary artery ligation ( n = 12) or sham ( n = 11) surgery followed by serial exercise tests and echocardiography for 16 wk post-MI. LV pressure-volume relationships were determined using a blood-perfused Langendorff preparation. Exercise capacity was 60% of shams immediately post-MI ( P < 0.05) followed by a recovery to near normal during weeks 5– 8. Thereafter, there was a progressive decline in exercise capacity to ±40% of shams ( P < 0.01). At both 8 and 16 wk post-MI, fractional shortening (FS) was reduced and end-diastolic diameter (EDD) was increased ( P < 0.01). However, neither FS nor EDD correlated with exercise at 8 or 16 wk ( r2 < 0.12, P > 0.30). LV septal wall thickness was increased at both 8 ( P = 0.17 vs. shams) and 16 wk ( P = 0.035 vs. shams) post-MI and correlated with exercise at both times ( r2 ≥ 0.50 and P ≤ 0.02 at 8 and 16 wk). Neither end-diastolic volume nor maximum LV developed pressure at 16 wk correlated with exercise capacity. Exercise capacity follows a biphasic time course post-MI. An immediate decrease is followed by an early recovery phase that is associated with compensatory LV hypertrophy. Subsequently, there is a progressive decrease in exercise capacity that is independent of further changes in LV volume or contractile function.

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Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function

10.2337/figshare.13342229 ◽

2020 ◽

Author(s):

Ada Admin ◽

Federico Cividini ◽

Brian T Scott ◽

Jorge Suarez ◽

Darren E. Casteel ◽

...

Keyword(s):

Contractile Function ◽

Pyruvate Dehydrogenase Complex ◽

Dominant Negative ◽

Diabetic Heart ◽

Acid Oxidation ◽

Cardiac Contractile Function ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Type 2 Diabetic

The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9 (dCas9)-based gene promoter pull-down approach coupled with mass spectrometry we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor co-repressor 2 (Ncor2) repression, and ChIP assays identified PPARα as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca2+ uptake and impairs mitochondrial energy production via glucose oxidation, by depressing Pyruvate Dehydrogenase Complex (PDC) activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUbW246R/V251E) in vivo rescued T2D cardiomyocytes from metabolic inflexibility, and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban (PLN) phosphorylation via Protein Kinase A (PKA). We conclude that MCUb represents one newly-discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically-stressed diabetic heart.

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Nrf2 affects the efficiency of mitochondrial fatty acid oxidation

Biochemical Journal ◽

10.1042/bj20130863 ◽

2014 ◽

Vol 457 (3) ◽

pp. 415-424 ◽

Cited By ~ 116

Author(s):

Marthe H. R. Ludtmann ◽

Plamena R. Angelova ◽

Ying Zhang ◽

Andrey Y. Abramov ◽

Albena T. Dinkova-Kostova

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Saturated Fatty Acids ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Atp Production ◽

Mitochondrial Fatty Acid ◽

Mitochondrial Oxidation ◽

Long Chain

Transcription factor Nrf2 affects fatty acid oxidation; the mitochondrial oxidation of long-chain (palmitic) and short-chain (hexanoic) saturated fatty acids is depressed in the absence of Nrf2 and accelerated when Nrf2 is constitutively activated, affecting ATP production and FADH2 utilization.

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Macrophage Activities in Myocardial Infarction and Heart Failure

Cardiology Research and Practice ◽

10.1155/2020/4375127 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Sophia Esi Duncan ◽

Shan Gao ◽

Michael Sarhene ◽

Joel Wake Coffie ◽

Deng Linhua ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Left Ventricular Systolic Dysfunction ◽

Heart Diseases ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Hibernating Myocardium ◽

Clear Understanding ◽

Myocardial Repair

Heart diseases remain the major cause of death worldwide. Advances in pharmacological and biomedical management have resulted in an increasing proportion of patients surviving acute heart failure (HF). However, many survivors of HF in the early stages end up increasing the disease to chronic HF (CHF). HF is an established frequent complication of myocardial infarction (MI), and numerous influences including persistent myocardial ischemia, shocked myocardium, ventricular remodeling, infarct size, and mechanical impairments, as well as hibernating myocardium trigger the development of left ventricular systolic dysfunction following MI. Macrophage population is active in inflammatory process, yet the clear understanding of the causative roles for these macrophage cells in HF development and progression is actually incomplete. Long ago, it was thought that macrophages are of importance in the heart after MI. Also, though inflammation is as a result of adverse HF in patients, but despite the fact that broad immunosuppression therapeutic target has been used in various clinical trials, no positive results have showed up, but rather, the focus on proinflammatory cytokines has proved more benefits in patients with HF. Therefore, in this review, we discuss the recent findings and new development about macrophage activations in HF, its role in the healthy heart, and some therapeutic targets for myocardial repair. We have a strong believe that there is a need to give maximum attention to cardiac resident macrophages due to the fact that they perform various tasks in wound healing, self-renewal of the heart, and tissue remodeling. Currently, it has been discovered that the study of macrophages goes far beyond its phagocytotic roles. If researchers in future confirm that macrophages play a vital role in the heart, they can be therapeutically targeted for cardiac healing.

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Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00434.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1847-H1860 ◽

Cited By ~ 114

Author(s):

Marina R. Bergman ◽

John R. Teerlink ◽

Rajeev Mahimkar ◽

Luyi Li ◽

Bo-Qing Zhu ◽

...

Keyword(s):

Transgenic Mice ◽

Matrix Metalloproteinase ◽

Ventricular Remodeling ◽

Systolic Function ◽

Systolic Dysfunction ◽

Systolic Pressure ◽

Left Ventricular ◽

Matrix Metalloproteinase 2 ◽

Membrane Type ◽

Volume Relation

Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the α-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 ± 3 vs. MMP 51 ± 12 μl; P = 0.003] and systolic (C 7 ± 2 vs. MMP 28 ± 14 μl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 ± 4 vs. MMP 23 ± 3 μl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 ± 7% vs. MMP 48 ± 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 ± 84 vs. MMP 78 ± 49 mW/μl2; P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 ± 1.5 vs. MMP 4.7 ± 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury.

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Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.267.5.h1862 ◽

1994 ◽

Vol 267 (5) ◽

pp. H1862-H1871 ◽

Cited By ~ 27

Author(s):

R. L. Collins-Nakai ◽

D. Noseworthy ◽

G. D. Lopaschuk

Keyword(s):

Fatty Acid ◽

Glucose Metabolism ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Contractile Function ◽

Pyruvate Dehydrogenase Complex ◽

Active Form ◽

Acid Oxidation ◽

Complex Activity ◽

Atp Production

Although epinephrine is widely used clinically, its effect on myocardial energy substrate preference in the intact heart has yet to be clearly defined. We determined the effects of epinephrine on glucose and fatty acid metabolism in isolated working rat hearts perfused with 11 mM glucose, 0.4 mM palmitate, and 100 muU/ml insulin at an 11.5-mmHg left atrial preload and a 60-mmHg aortic afterload. Glycolysis and glucose oxidation were measured in hearts perfused with [5–3H]glucose and [U-14C]glucose, whereas fatty acid oxidation was measured in hearts perfused with [1–14C]palmitate. Addition of 1 microM epinephrine resulted in a 53% increase in the heart rate-developed pressure product. Glycolysis increased dramatically following addition of epinephrine (a 272% increase), as did glucose oxidation (a 410% increase). In contrast, fatty acid oxidation increased by only 10%. Epinephrine treatment did not increase the amount of oxygen required to produce an equivalent amount of ATP; however, epinephrine did increase the uncoupling between glycolysis and glucose oxidation in these fatty acid-perfused hearts, resulting in a significant increase in H+ production from glucose metabolism. Overall ATP production in epinephrine-treated hearts increased 59%. The contribution of glucose (glycolysis and glucose oxidation) to ATP production increased from 13 to 36%, which was accompanied by a reciprocal decrease in the contribution of fatty acid oxidation to ATP production from 83 to 63%. The increase in glucose oxidation was accompanied by a significant increase in pyruvate dehydrogenase complex activity in the active form. We conclude that the increase in ATP required for contractile function following epinephrine treatment occurs through a preferential increase in glucose use.

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