Dimethyl fumarate preserves left ventricular infarct integrity following myocardial infarction via modulation of cardiac macrophage and fibroblast oxidative metabolism
Graphical abstract
Introduction
Approximately 1 million US citizens experience a myocardial infarction (MI) each year. MI is characterized by an acute inflammatory response, followed by remodeling of the left ventricle (LV) and formation of a collagenous scar [1,2]. It has recently been demonstrated clinically that targeting inflammation is an effective strategy to attenuate deleterious post-MI outcomes [3]. Both macrophages and fibroblasts play crucial roles in remodeling of the left ventricle, and therapeutic strategies have aimed at shifting these cell types towards reparative rather than inflammatory phenotypes [4]. Modulating cellular metabolism from glycolysis towards oxidative phosphorylation (OXPHOS) promotes anti-inflammatory and pro-reparative macrophage and fibroblast phenotypes [[5], [6], [7], [8]].
Dimethyl fumarate (DMF) is an anti-inflammatory drug clinically approved for treatment of psoriasis and multiple sclerosis (MS), and exerts cardioprotective actions in rodent models of MI [9,10]. Recently, a novel role of DMF was discovered in its ability to covalently succinate glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and inhibit its activity in activated macrophages during progression of MS [11]. However, whether DMF exerts cardioprotective actions after MI by modulating macrophage and fibroblast metabolism has not been previously investigated. Thus, we hypothesized that DMF would protect against MI-induced cardiac injury by promoting reparative macrophage and fibroblast phenotypes via metabolic reprogramming in these cell types.
Section snippets
Mouse model of myocardial infarction and DMF treatment
All procedures were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center. Surgical ligation of the left coronary artery was performed to produce MI in adult male C57BL/6J mice (4–5 months age) as described previously [1,4]. Mice were anesthetized with 2% isoflurane, and intubated through the trachea and connected to a ventilator. A small incision was made on the left flank, and the heart was visualized between the 3rd and 4th ribs. The left
DMF improves LV functional outcomes and pulmonary congestion after MI
Day 7 survival and infarct size were not significantly different between groups (Fig. 1A). At day 7 in surviving mice, DMF significantly attenuated thinning of both the infarcted and non-infarcted walls, and attenuated LV dilation as assessed by the end-diastolic volume, while not affecting ejection fraction (Fig. 1B). DMF did not affect LV or RV mass (normalized to tibia length), but significantly decreased lung wet and dry mass (Fig. 1C). DMF also improved ejection fraction at day 3, and
Discussion
Our results indicate that DMF improves infarct remodeling through actions on macrophages and fibroblasts, two of the major cell types that directly and actively participate in remodeling of the infarcted myocardium. In both cell types, DMF inhibited pro-inflammatory phenotypes, and increased collagen deposition and attenuated infarct wall thinning through activation of a myofibroblast phenotype, without promoting fibrosis in the remote myocardium. In infarct macrophages, DMF promoted
Conclusions
In conclusion, our results demonstrate that DMF, a clinically approved anti-inflammatory agent, improves post-MI LV remodeling and heart failure outcomes via novel metabolic mechanisms in cardiac macrophages and fibroblasts. Our study provides important therapeutic implications for the rapidly blossoming fields of non-myocyte metabolism in the injured heart.
Funding sources
The authors' research was supported by National Heart, Lung, and Blood Institute (P01 HL51971), National Institute of General Medical Sciences (P20 GM104357 and U54 GM115428), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK121411), and the American Heart Association (18POST34000039).
Declarations of interest
None.
Acknowledgments
We acknowledge the excellent contributions of the UMMC Histology Core and Molecular and Genomics Core.
References (43)
Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway
Cell Metab.
(2012)Dimethyl fumarate, a small molecule drug for psoriasis, inhibits nuclear factor-kappaB and reduces myocardial infarct size in rats
Eur. J. Pharmacol.
(2008)Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the Warburg effect in LPS-activated macrophages
Cell Metab.
(2015)Inflammatory cardiac fibroblast phenotype underlies chronic alcohol-induced cardiac atrophy and dysfunction
Life Sci.
(2020)Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning
Biochim. Biophys. Acta
(2011)NRF2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming
Cell Rep.
(2016)Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes
Matrix Biol.
(2019)- et al.
Fibroblasts in myocardial infarction: a role in inflammation and repair
J. Mol. Cell. Cardiol.
(2014) Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts
Toxicol. Appl. Pharmacol.
(2011)Exposure to chronic alcohol accelerates development of wall stress and eccentric remodeling in rats with volume overload
J. Mol. Cell. Cardiol.
(2016)
Mapping macrophage polarization over the myocardial infarction time continuum
Basic Res. Cardiol.
Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding
Am. J. Physiol. Heart Circ. Physiol.
Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure
Circulation
Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis
Basic Res. Cardiol.
Noninvasive immunometabolic cardiac inflammation imaging using hyperpolarized magnetic resonance
Circ. Res.
Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair
Cell Metab.
Epigenetic metabolic reprogramming of right ventricular fibroblasts in pulmonary arterial hypertension: a pyruvate dehydrogenase kinase-dependent shift in mitochondrial metabolism promotes right ventricular fibrosis
Circ. Res.
Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation
Nat. Commun.
Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity
Science
Targeting the glucagon receptor improves cardiac function and enhances insulin sensitivity following a myocardial infarction
Cardiovasc. Diabetol.
HIF1alpha-induced glycolysis metabolism is essential to the activation of inflammatory macrophages
Mediat. Inflamm.
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