GW28-e0941 Increasing fatty acid utilization improves cardiac function through OPA1-mediated mitochondrial fusion in pressure overload-induced heart failure

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

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Abstract 255: Novel Role for Free Fatty Acid Receptor 4 in Response to Pathologic Pressure Overload-Induced Heart Failure in Mice

Circulation Research ◽

10.1161/res.125.suppl_1.255 ◽

2019 ◽

Vol 125 (Suppl_1) ◽

Author(s):

Katherine A Murphy ◽

Sonal S Joshi ◽

Chastity L Healy ◽

Katherine M Ernste ◽

Brian A Harsch ◽

...

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Free Fatty Acid ◽

Pressure Overload ◽

Acid Receptor ◽

Free Fatty Acid Receptor ◽

Fatty Acid Receptor

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Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720065115 ◽

2018 ◽

Vol 115 (20) ◽

pp. E4661-E4669 ◽

Cited By ~ 35

Author(s):

Xudong Liao ◽

Yuyan Shen ◽

Rongli Zhang ◽

Keiki Sugi ◽

Neelakantan T. Vasudevan ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Late Phase ◽

Myeloid Cells ◽

Pressure Overload ◽

Genetic Mutations ◽

Nonischemic Cardiomyopathy ◽

Resident Macrophage ◽

Temporal And Spatial

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

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Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

Cardiovascular Research ◽

10.1093/cvr/cvx016 ◽

2017 ◽

Vol 113 (6) ◽

pp. 633-643 ◽

Cited By ~ 21

Author(s):

Jihe Li ◽

Keyvan Yousefi ◽

Wen Ding ◽

Jayanti Singh ◽

Lina A. Shehadeh

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Cardiomyocyte Hypertrophy ◽

Therapeutic Effects ◽

Rna Aptamer ◽

Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

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Regional myocardial free fatty acid utilization following carvedilol therapy in patients with heart failure

Journal of Molecular and Cellular Cardiology ◽

10.1016/s0022-2828(01)90692-3 ◽

2001 ◽

Vol 33 (6) ◽

pp. A180

Author(s):

T.R. Wallhaus ◽

M. Taylor ◽

D.C. Russell ◽

T.R. DeGrado ◽

R.J. Nickles ◽

...

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Free Fatty Acid ◽

Fatty Acid Utilization ◽

Patients With Heart Failure

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A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00599.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. H1585-H1593 ◽

Cited By ~ 34

Author(s):

David J. Chess ◽

Ramzi J. Khairallah ◽

Karen M. O'Shea ◽

Wenhong Xu ◽

William C. Stanley

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Cardiac Hypertrophy ◽

High Fat Diet ◽

Citrate Synthase ◽

Pressure Overload ◽

Left Ventricular ◽

Oxidative Enzymes ◽

High Fat ◽

Low Fat Diet

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice ( n = 10–12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (∼70%) and end-systolic and end-diastolic areas (∼100% and ∼45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.

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Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction

10.1101/2021.08.31.458367 ◽

2021 ◽

Author(s):

Igor N Zelko ◽

Sujith Dassanayaka ◽

Marina V Malovichko ◽

Caitlin M Howard ◽

Lauren F Garrett ◽

...

Keyword(s):

Heart Failure ◽

Endothelial Cells ◽

Cardiac Function ◽

Cardiac Tissue ◽

Pressure Overload ◽

Endothelial Activation ◽

Air Exposure ◽

Benzene Exposure ◽

Increased Risk

Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5-2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.

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