Publications by authors named "Outi Villet"

9 Publications

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Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts.

J Mol Cell Cardiol 2021 May 12;158:1-10. Epub 2021 May 12.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Republican Street 850, 98109 Seattle, WA, USA. Electronic address:

Background: Reduced fatty acid oxidation (FAO) is a hallmark of metabolic remodeling in heart failure. Enhancing mitochondrial long-chain fatty acid uptake by Acetyl-CoA carboxylase 2 (ACC2) deletion increases FAO and prevents cardiac dysfunction during chronic stresses, but therapeutic efficacy of this approach has not been determined.

Methods: Male and female ACC2 f/f-MCM (ACC2KO) and their respective littermate controls were subjected to chronic pressure overload by TAC surgery. Tamoxifen injection 3 weeks after TAC induced ACC2 deletion and increased FAO in ACC2KO mice with pathological hypertrophy.

Results: ACC2 deletion in mice with pre-existing cardiac pathology promoted FAO in female and male hearts, but improved cardiac function only in female mice. In males, pressure overload caused a downregulation in the mitochondrial oxidative function. Stimulating FAO by ACC2 deletion caused unproductive acyl-carnitine accumulation, which failed to improve cardiac energetics. In contrast, mitochondrial oxidative capacity was sustained in female pressure overloaded hearts and ACC2 deletion improved myocardial energetics. Mechanistically, we revealed a sex-dependent regulation of PPARα signaling pathway in heart failure, which accounted for the differential response to ACC2 deletion.

Conclusion: Metabolic remodeling in the failing heart is sex-dependent which could determine the response to metabolic intervention. The findings suggest that both mitochondrial oxidative capacity and substrate preference should be considered for metabolic therapy of heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2021.05.004DOI Listing
May 2021

Acetylation of muscle creatine kinase negatively impacts high-energy phosphotransfer in heart failure.

JCI Insight 2021 02 8;6(3). Epub 2021 Feb 8.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, and.

A hallmark of impaired myocardial energetics in failing hearts is the downregulation of the creatine kinase (CK) system. In heart failure patients and animal models, myocardial phosphocreatine content and the flux of the CK reaction are negatively correlated with the outcome of heart failure. While decreased CK activity is highly reproducible in failing hearts, the underlying mechanisms remains elusive. Here, we report an inverse relationship between the activity and acetylation of CK muscle form (CKM) in human and mouse failing hearts. Hyperacetylation of recombinant CKM disrupted MM homodimer formation and reduced enzymatic activity, which could be reversed by sirtuin 2 treatment. Mass spectrometry analysis identified multiple lysine residues on the MM dimer interface, which were hyperacetylated in the failing hearts. Molecular modeling of CK MM homodimer suggested that hyperacetylation prevented dimer formation through interfering salt bridges within and between the 2 monomers. Deacetylation by sirtuin 2 reduced acetylation of the critical lysine residues, improved dimer formation, and restored CKM activity from failing heart tissue. These findings reveal a potentially novel mechanism in the regulation of CK activity and provide a potential target for improving high-energy phosphoryl transfer in heart failure.
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http://dx.doi.org/10.1172/jci.insight.144301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934860PMC
February 2021

Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy.

Circulation 2020 Sep 29;142(10):983-997. Epub 2020 Jun 29.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (D.S., S.C.K., P.W., N.D.R., O.V., K.N., Y.-W.A.H., A.C., W.W., R.T.), University of Washington, Seattle.

Background: Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acid transport into mitochondria via deletion of acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy in nonobese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology-associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity-induced cardiomyopathy, and if so, to elucidate the underlying mechanisms.

Methods: We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen-inducible model (ACC2 iKO). Control and ACC2 iKO mice were subjected to high-fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function, and mitophagy activity were examined.

Results: Despite both control and ACC2 iKO mice exhibiting a similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD-induced cardiac dysfunction, pathological remodeling, and mitochondria dysfunction, as well. Similarly, increasing FAO by knockdown of ACC2 prevented palmitate-induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was attenuated, in part, in the ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD-induced downregulation of parkin. During stimulation for mitophagy, mitochondria-localized parkin was severely reduced in control HFD-fed mouse heart, which was restored, in part, in ACC2 iKO HFD-fed mice.

Conclusions: These data show that increasing cardiac FAO alone does not cause cardiac dysfunction, but protects against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD-induced obesity is mediated, in part, by the maintenance of mitochondria function through regulating parkin-mediated mitophagy. Our findings also suggest that targeting the parkin-dependent mitophagy pathway could be an effective strategy against the development of obesity-induced cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484440PMC
September 2020

Enhancing fatty acid oxidation negatively regulates PPARs signaling in the heart.

J Mol Cell Cardiol 2020 09 24;146:1-11. Epub 2020 Jun 24.

Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA 98109, USA. Electronic address:

High fatty acid oxidation (FAO) is associated with lipotoxicity, but whether it causes lipotoxic cardiomyopathy remains controversial. Molecular mechanisms that may be responsible for FAO-induced lipotoxic cardiomyopathy are also elusive. In this study, increasing FAO by genetic deletion of acetyl-CoA carboxylase 2 (ACC2) did not induce cardiac dysfunction after 16 weeks of high fat diet (HFD) feeding. This suggests that increasing FAO, per se, does not cause metabolic cardiomyopathy in obese mice. We compared transcriptomes of control and ACC2 deficient mouse hearts under chow- or HFD-fed conditions. ACC2 deletion had a significant impact on the global transcriptome including downregulation of the peroxisome proliferator-activated receptors (PPARs) signaling and fatty acid degradation pathways. Increasing fatty acids by HFD feeding normalized expression of fatty acid degradation genes in ACC2 deficient mouse hearts to the same level as the control mice. In contrast, cardiac transcriptome analysis of the lipotoxic mouse model (db/db) showed an upregulation of PPARs signaling and fatty acid degradation pathways. Our results suggest that enhancing FAO by genetic deletion of ACC2 negatively regulates PPARs signaling through depleting endogenous PPAR ligands, which can serve as a negative feedback mechanism to prevent excess activation of PPAR signaling under non-obese condition. In obesity, excessive lipid availability negates the feedback mechanism resulting in over activation of PPAR cascade, thus contributes to the development of cardiac lipotoxicity.
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http://dx.doi.org/10.1016/j.yjmcc.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494556PMC
September 2020

Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis.

Circ Res 2020 01 11;126(2):182-196. Epub 2019 Nov 11.

From the Department of Anesthesiology and Pain Medicine (J.R., S.Y., O.V., D.S., Y.-W.A.H., S.C.K., R.T.), Mitochondria and Metabolism Center, University of Washington, Seattle.

Rationale: Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics.

Objective: The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.

Methods And Results: We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy.

Conclusions: Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315483DOI Listing
January 2020

Glucose promotes cell growth by suppressing branched-chain amino acid degradation.

Nat Commun 2018 07 26;9(1):2935. Epub 2018 Jul 26.

Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, 98109, USA.

Glucose and branched-chain amino acids (BCAAs) are essential nutrients and key determinants of cell growth and stress responses. High BCAA level inhibits glucose metabolism but reciprocal regulation of BCAA metabolism by glucose has not been demonstrated. Here we show that glucose suppresses BCAA catabolism in cardiomyocytes to promote hypertrophic response. High glucose inhibits CREB stimulated KLF15 transcription resulting in downregulation of enzymes in the BCAA catabolism pathway. Accumulation of BCAA through the glucose-KLF15-BCAA degradation axis is required for the activation of mTOR signaling during the hypertrophic growth of cardiomyocytes. Restoration of KLF15 prevents cardiac hypertrophy in response to pressure overload in wildtype mice but not in mutant mice deficient of BCAA degradation gene. Thus, regulation of KLF15 transcription by glucose is critical for the glucose-BCAA circuit which controls a cascade of obligatory metabolic responses previously unrecognized for cell growth.
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http://dx.doi.org/10.1038/s41467-018-05362-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062555PMC
July 2018

The effects of fatty acid composition on cardiac hypertrophy and function in mouse models of diet-induced obesity.

J Nutr Biochem 2017 08 25;46:137-142. Epub 2017 May 25.

Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA. Electronic address:

High-fat diets (HFDs) are used frequently to study the development of cardiac dysfunction in animal models of obesity and diabetes. However, impairment in systolic function, often reported as declining ejection fraction, may not consistently occur in a given time frame which could be contributable to a variety of factors within the experimental design. One major factor may be the amounts of saturated and unsaturated fatty acids (FAs) that are present in the diet. To determine whether the FA content and composition were critical determinants in the development of cardiac dysfunction in response to high-fat feeding, we fed adult, male mice Western diet (45% fat, 60% saturated), Surwit diet (60% fat, 90% saturated), milk-fat-based diet (60% fat, 60% saturated) or high-fat Western diet (HFWD, 60% fat, 32% saturated) for 12 weeks. We report that neither the amount of total fat nor the ratio of saturated to unsaturated FAs in the diets differentially affects body weight and adiposity in mice. In addition, no evidence of systolic dysfunction is present after 12 weeks. Interestingly, the HFWD, with equal parts saturated, monounsaturated and polyunsaturated FAs, induces mild cardiac hypertrophy and diastolic dysfunction after 12 weeks, which coincides with elevated serum levels of arachidonic acid. Our results suggest that the dietary FA content and composition may be a primary determinant of diastolic, but not systolic, dysfunction in animal models of diet-induced obesity.
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http://dx.doi.org/10.1016/j.jnutbio.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516950PMC
August 2017

Optimal protective hypothermia in arrested mammalian hearts.

Ther Hypothermia Temp Manag 2015 Mar 16;5(1):40-7. Epub 2014 Dec 16.

1 Division of Cardiology, Department of Pediatrics, University of Washington , Seattle, Washington.

Many therapeutic hypothermia recommendations have been reported, but the information supporting them is sparse, and reveals a need for the data of target therapeutic hypothermia (TTH) from well-controlled experiments. The core temperature ≤35°C is considered as hypothermia, and 29°C is a cooling injury threshold in pig heart in vivo. Thus, an optimal protective hypothermia (OPH) should be in the range 29-35°C. This study was conducted with a pig cardiopulmonary bypass preparation to decrease the core temperature to 29-35°C range at 20 minutes before and 60 minutes during heart arrest. The left ventricular (LV) developed pressure, maximum of the first derivative of LV (dP/dtmax), cardiac power, heart rate, cardiac output, and myocardial velocity (Vmax) were recorded continuously via an LV pressure catheter and an aortic flow probe. At 20 minutes of off-pump during reperfusion after 60 minutes arrest, 17 hypothermic hearts showed that the recovery of Vmax and dP/dtmax established sigmoid curves that consisted of two plateaus: a good recovery plateau at 29-30.5°C, the function recovered to baseline level (BL) (Vmax=118.4%±3.9% of BL, LV dP/dtmax=120.7%±3.1% of BL, n=6); another poor recovery plateau at 34-35°C (Vmax=60.2%±2.8% of BL, LV dP/dtmax=28.0%±5.9% of BL, p<0.05, n=6; ), which are similar to the four normothermia arrest (37°C) hearts (Vmax=55.9%±4.8% of BL, LV dP/dtmax=24.5%±2.1% of BL, n=4). The 32-32.5°C arrest hearts showed moderate recovery (n=5). A point of inflection (around 30.5-31°C) existed at the edge of a good recovery plateau followed by a steep slope. The point presented an OPH that should be the TTH. The results are concordant with data in the mammalian hearts, suggesting that the TTH should be initiated to cool core temperature at 31°C.
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http://dx.doi.org/10.1089/ther.2014.0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340649PMC
March 2015

Advances in cell transplantation therapy for diseased myocardium.

Stem Cells Int 2011 28;2011:679171. Epub 2011 Jun 28.

Department of Cardiothoracic Surgery, University of Helsinki Meilahti Hospital, P.O. Box 340, FIN-00029 HUS, Finland.

The overall objective of cell transplantation is to repopulate postinfarction scar with contractile cells, thus improving systolic function, and to prevent or to regress the remodeling process. Direct implantation of isolated myoblasts, cardiomyocytes, and bone-marrow-derived cells has shown prospect for improved cardiac performance in several animal models and patients suffering from heart failure. However, direct implantation of cultured cells can lead to major cell loss by leakage and cell death, inappropriate integration and proliferation, and cardiac arrhythmia. To resolve these problems an approach using 3-dimensional tissue-engineered cell constructs has been investigated. Cell engineering technology has enabled scaffold-free sheet development including generation of communication between cell graft and host tissue, creation of organized microvascular network, and relatively long-term survival after in vivo transplantation.
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http://dx.doi.org/10.4061/2011/679171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138051PMC
November 2011