Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy

Flam, Emily; Jang, Cholsoon; Murashige, Danielle; Yang, Yifan; Morley, Michael; Jung, Sunhee; Kantner, Daniel S.; Pepper, Hannah L.; Bedi, Kenneth; Brandimarto, Jeff; Prosser, Benjamin L.; Cappola, Thomas P.; Snyder, Nathaniel W.; Rabinowitz, Joshua D.; Margulies, Kenneth B.; Arany, Zoltàn

doi:10.1038/s44161-022-00117-6

Cited by 34 publications

(43 citation statements)

References 64 publications

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“…3E&F). This finding is in line with a recent study reporting increased oxidation of ketone bodies and amino acids in failing human hearts 57,58 , implicating loss of GILT in the heart accelerates HF progression.…”

Section: Resultssupporting

confidence: 92%

Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure

Wang

Qian

et al. 2022

Preprint

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Heart failure (HF) remains the leading cause of death globally. The progression of HF is characterized by cardiac mitochondrial dysfunction and aberrant inflammatory responses. Although the lysosome has been recognized as the central player for maintaining immuno-metabolic homeostasis in diverse organs in health and disease, the mechanistic insights into the regulation of lysosome-dependent immuno-metabolism in the heart are lacking. Lysosomal reductase Gamma Interferon-Inducible Thiol Reductase (GILT) is the only identified lysosomal reductase that controls more than 11 lysosomal enzymes, and a single nucleotide polymorphism in the coding sequence of GILT has been implicated in promoting cardiovascular risk. Here, we show that GILT expression and activity are reduced in hearts from human patients and mice with HF, respectively. Moreover, cardiomyocyte-specific deletion of GILT (GILT-cKO) results in left ventricular remodeling and dysfunction in the setting of pressure overload. At the cellular level, cardiac GILT deficiency leads to impaired mitochondrial respiration, elevated mitochondrial oxidative stress, and increased NLR Family Pyrin Domain Containing 3(NLRP3)-dependent inflammation in the heart. Mechanistically, inhibition of NLRP3 in primary cardiomyocytes ameliorated the mitochondrial dysfunction in the GILT deficient cells, implicating a causative role of the lysosome-inflammasome axis on regulating cardiac mitochondrial function. Together, these findings elucidate a functional link between cardiac lysosomes, inflammatory responses and mitochondrial respiration. Knowledge gained from this study might speed the development of therapeutic agents to treat patients with HF.

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Section: Resultssupporting

confidence: 92%

Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure

Wang

Qian

et al. 2022

Preprint

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“…The T2D-DL group had the highest levels of acylcarnitines, with subjects in the T2D-M group having similar levels to those in the ND group. Acylcarnitines have previously been reported as a proxy for fatty acid metabolism, with increased levels in circulation indicating β-oxidation dysfunction (Strand et al, 2017;Flam et al, 2022). This result is consistent with previous studies indicating that individuals with T2D have increased levels of short, medium, and long-chain acylcarnitines (Sun et al, 2016;Strand et al, 2017), which are reflective of cardiac metabolism (Makrecka-Kuka et al, 2017).…”

Section: Metabolites Associated With Cvd Risk Are Reduced With Metfor...supporting

confidence: 90%

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort

Wancewicz

Zhu

Fenske

et al. 2023

J Pharmacol Exp Ther

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Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide, metformin, is the most common pharmaceutical therapy. Yet, it's full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of non-diabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared to nondiabetic subjects: changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. Significance Statement:This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

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“…Because Fatty Acid Oxidation (FAO) and ETC pathways were identified in our porcine analysis and alterations in these pathways are present in human heart failure(23,24), we evaluated and compared the relative changes in FAO and ETC in rodents (GSE119754, PXD027273), pigs, and humans (GSE198618) (10,11,25). In the proteomics analysis, abundances of nearly all FAO and ETC proteins were reduced in MCT rats as compared to control rats ( Figure 6A-B ).…”

Section: Resultsmentioning

confidence: 99%

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

Mendelson

Sternbach

Doyle

et al. 2023

Preprint

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Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

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Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy

Cited by 34 publications

References 64 publications

Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure

Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

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