Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Distinct lipidomic profiles in models of physiological and pathological cardiac remodeling, and potential therapeutic strategies
Graphical abstract
Introduction
The heart undergoes significant remodeling in response to pathological stimuli (e.g. hypertension) and physiological stimuli (e.g. chronic exercise training). In both cases, cardiac myocyte membranes must remodel dramatically [1]. It is now well recognized that major components of the membrane lipid bilayer such as phospholipids and sphingolipids have structural roles but also regulate signaling pathways and have functional consequences [2]. Thus, changes to the quantity and types of lipid species in the heart have the potential to alter cardiac function and growth [1]. Pathological and physiological cardiac remodeling are associated with very distinct phenotypes. Pathological remodeling is typically characterized by cardiac myocyte loss, fibrosis and cardiac dysfunction [3]. In contrast, physiological remodeling is characterized by cardiac enlargement associated with cell survival and normal heart function [4]. It is also recognized that pathological and physiological remodeling can be mediated by the activation of distinct signaling cascades and are associated with distinct molecular signatures (mRNAs, microRNAs, proteins). Identifying and targeting distinct regulators of physiological and pathological remodeling is considered a promising therapeutic strategy for the failing heart. GPCR-calcineurin-NFAT pathways are considered important mediators of pathological remodeling whereas the IGF1-PI3K-Akt pathway is the key signaling cascade responsible for physiological cardiac remodeling [3], [4]. Mice with increased cardiac IGF1-PI3K signaling develop physiological cardiac hypertrophy which is associated with normal or enhanced heart function. We hypothesized that lipid species are differentially regulated in response to physiological and pathological cardiac stimuli and signaling, and contribute to the distinct phenotypes and outcomes associated with physiological and pathological remodeling.
To date, there have been a small number of studies which have examined lipid species in models of pathological remodeling such as pressure overload and myocardial infarction (MI) [1], [5], [6], [7], [8], but to our knowledge there are no studies which have comprehensively studied lipid species in models of physiological cardiac remodeling. Furthermore, technological advancements in mass spectrometry now allow for more comprehensive lipidomic profiling. The main aims of this study were: 1) to assess whether lipid species are altered in the heart by a key signaling pathway that regulates physiological cardiac growth and remodeling (i.e. IGF1-PI3K), 2) to examine if lipid classes regulated by PI3K are differentially regulated in a model with pathological remodeling and dysfunction, and 3) to determine whether modulating PI3K-regulated lipids can restore cardiac defects.
Here, we identify distinct lipidomic profiles in mouse models with differential cardiac PI3K activity and cardiac disease. Plasmalogens were a class of lipids identified to be lower in hearts of mice with reduced PI3K activity and small hearts (depressed physiological cardiac remodeling), as well as mice with cardiac disease. A dietary supplementation strategy successfully restored some key plasmalogen species, but had no significant impact on restoring heart size or function. This may be due to the concurrent repression of other plasmalogen species in the heart. This study increases our understanding of lipid species differentially regulated in models of physiological and pathological cardiac remodeling, and highlights the need to further understand the role and regulation of plasmalogens, and other lipid species in the heart.
Section snippets
Experimental animals
Animal care and experimentation were approved by the Alfred Health and Education Precinct Animal Ethics Committee. Mice were housed in a 12 h light-dark cycle, temperature-controlled environment in the Alfred Medical Research and Education Precinct Animal Centre. Body weight was recorded weekly. Mice were euthanized at the end of the study. Tissues and plasma were collected for molecular and lipidomic analyses.
Transgenic (Tg) mouse models
Tg mice were maintained on a FVB/N or C57BL/6 background as specified. Tg mice were
Distinct lipid profiles in mice with differential cardiac PI3K activity
Lipid profiling was performed on hearts of cardiac-specific Tg mice with differential regulation of the IGF1R-PI3K pathway. IGF1R and caPI3K mice develop physiological hypertrophy due to increased PI3K activity. Conversely, dnPI3K mice have smaller hearts due to reduced PI3K activity [9], [10]. In the current study, caPI3K and IGF1R Tg mice showed an increase in heart size (heart weight/tibia length ratio; HW/TL) compared to Ntg mice (Fig. 1a, b). Consistent with the induction of physiological
Discussion
Lipidomic profiling is an extremely powerful tool that has been increasingly used to uncover potential biomarkers and therapeutic targets in a variety of diseases [34], [35], [36], [37]. The major goal of this study was to first identify differentially regulated lipid species in the hearts of mouse models with physiological and pathological cardiac remodeling, and next, to assess whether manipulating lipid species with an intervention could restore cardiac defects. Here, we identified
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Acknowledgments
This study was funded by National Health and Medical Research Council Project Grant (APP1045585 to J.R.M) and also supported in part by the Victorian Government Operational Infrastructre Support program. P.J.M. and J.R.M are National Health and Medical Research Council Senior Research Fellows (IDs 1042095, 586604, 1078985). J.R.M was also supported by an Australian Research Council Future Fellowship (FT0001657). K·H was supported jointly by an Alzheimer's Australia Dementia Research Foundation
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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2021, Journal of Sport and Health ScienceCitation Excerpt :As cardiac myocytes enlarge or change shape in response to a stimulus (e.g., cardiac stress such as hypertension or chronic exercise training), the plasma membrane which includes hundreds of lipid species, undergoes dramatic remodeling. Lipid profiling (>300 lipid species) demonstrated that lipid profiles differ substantially in models of physiological cardiac remodeling (swim training, caPI3K transgenic mice, and IGF1R transgenic mice), models of pathological remodeling (severe pressure overload due to transverse aortic constriction, a transgenic model of DCM, and mice with reduced cardiac PI3K activity and greater susceptibility to cardiac stress, i.e., dnPI3K transgenic).79,80 As an example, many sphingolipid species were decreased in the hearts of caPI3K mice and increased in the hearts of dnPI3K mice; by contrast, many phospholipids were increased in the hearts of caPI3K mice but decreased in dnPI3K mice.79
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2021, Biochemistry and Biophysics ReportsCitation Excerpt :Changes in phospholipids and sphingolipids have also been reported in AMI [25,26] and correlated with CVD incidence [27], mortality [28] or prognosis [29]. The change in phosphatidylcholine levels was correlated with the risk of CVD [30], while a decrease in plasmalogens levels has also been observed in the plasma of patients with AMI [31] and has been reported in cardiac remodelling and restoration of cardiac function [32]. Lipid changes associated with AMI and IR in cardiac tissue of animal models or cells included changes in the profile of glycerolipids, sphingolipids, and free fatty acids [33], as well as depletion of cardiolipins (CLs) [34].
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2019, Pharmacological ResearchCitation Excerpt :The aim of our present work was to define the possible cardiac metabolic changes that could be induced by the treatment with human relaxin-2, in order to be better aware of the possible implications for therapeutic approaches to the treatment or prevention of heart failure and other cardiometabolic diseases with this hormone. A metabolomics study of cardiac samples taken from control and relaxin-treated rats revealed that relaxin-2 induces significant changes in major components of the membrane lipid bilayer of cardiac cells, such as glycerophospholipids and sphingolipids, known to have structural roles and also regulate signaling pathways with functional effects on cardiac function [20–22]. These findings highlight the need to further understand the role of relaxin in the regulation of lipid species in the heart, in the context of future therapeutic strategies for the treatment of cardiac metabolic alterations in heart failure.
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2019, Progress in Lipid ResearchCitation Excerpt :There was a significant increase in the total plasmalogen levels in the heart following batyl alcohol supplementation although the increase was restricted to O-18:0 alkyl chain containing plasmalogen species with concurrent decreases in the O-16:0 and O-18:1 plasmalogen species. However, there was no effect on heart size or function by batyl alcohol supplementation [89]. These divergent responses to alkylglycerols with different alkyl chain lengths suggest that the composition of plasmalogens within a cell or tissue, in addition to the total plasmalogen levels, may be important for their capacity to attenuate metabolic disease.