Distinct lipidomic profiles in models of physiological and pathological cardiac remodeling, and potential therapeutic strategies

https://doi.org/10.1016/j.bbalip.2017.12.003Get rights and content

Highlights

  • Distinct lipid profiles in physiological and pathological heart remodeling

  • Reduced plasmalogens in mouse models with defects in cardiac growth or function

  • Batyl alcohol increased p18:0 plasmalogens but decreased p16:0 and p18:1 species.

  • Batyl alcohol supplementation had no effect on heart size or function.

  • Lipid regulation in the failing heart is complex but warrants further study.

Abstract

Cardiac myocyte membranes contain lipids which remodel dramatically in response to heart growth and remodeling. Lipid species have both structural and functional roles. Physiological and pathological cardiac remodeling have very distinct phenotypes, and the identification of molecular differences represent avenues for therapeutic interventions. Whether the abundance of specific lipid classes is different in physiological and pathological models was largely unknown. The aim of this study was to determine whether distinct lipids are regulated in settings of physiological and pathological remodeling, and if so, whether modulation of differentially regulated lipids could modulate heart size and function. Lipidomic profiling was performed on cardiac-specific transgenic mice with 1) physiological cardiac hypertrophy due to increased Insulin-like Growth Factor 1 (IGF1) receptor or Phosphoinositide 3-Kinase (PI3K) signaling, 2) small hearts due to depressed PI3K signaling (dnPI3K), and 3) failing hearts due to dilated cardiomyopathy (DCM). In hearts of dnPI3K and DCM mice, several phospholipids (plasmalogens) were decreased and sphingolipids increased compared to mice with physiological hypertrophy. To assess whether restoration of plasmalogens could restore heart size or cardiac function, dnPI3K and DCM mice were administered batyl alcohol (BA; precursor to plasmalogen biosynthesis) in the diet for 16 weeks. BA supplementation increased a major plasmalogen species (p18:0) in the heart but had no effect on heart size or function. This may be due to the concurrent reduction in other plasmalogen species (p16:0 and p18:1) with BA. Here we show that lipid species are differentially regulated in settings of physiological and pathological remodeling. Restoration of lipid species in the failing heart warrants further examination.

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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