Dimethyl fumarate preserves left ventricular infarct integrity following myocardial infarction via modulation of cardiac macrophage and fibroblast oxidative metabolism

https://doi.org/10.1016/j.yjmcc.2021.05.008Get rights and content

Highlights

  • Dimethyl fumarate (DMF) improves left ventricular (LV) function following myocardial infarction (MI).

  • DMF improves collagen deposition and angiogenesis in the infarcted LV.

  • DMF increases macrophage oxidative phosphorylation (OXPHOS) metabolism in association with decreased IL-1β expression.

  • DMF promotes a reparative cardiac myofibroblast phenotype in association with decreased OXPHOS metabolism.

Abstract

Myocardial infarction (MI) is one of the leading causes of mortality and cardiovascular disease worldwide. MI is characterized by a substantial inflammatory response in the infarcted left ventricle (LV), followed by transition of quiescent fibroblasts to active myofibroblasts, which deposit collagen to form the reparative scar. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is an important mechanism by which these cell types transition towards reparative phenotypes. Thus, we hypothesized that dimethyl fumarate (DMF), a clinically approved anti-inflammatory agent with metabolic actions, would improve post-MI remodeling via modulation of macrophage and fibroblast metabolism. Adult male C57BL/6J mice were treated with DMF (10 mg/kg) for 3–7 days after MI. DMF attenuated LV infarct and non-infarct wall thinning at 3 and 7 days post-MI, and decreased LV dilation and pulmonary congestion at day 7. DMF improved LV infarct collagen deposition, myofibroblast activation, and angiogenesis at day 7. DMF also decreased pro-inflammatory cytokine expression (Tnf) 3 days after MI, and decreased inflammatory markers in macrophages isolated from the infarcted heart (Hif1a, Il1b). In fibroblasts extracted from the infarcted heart at day 3, RNA-Seq analysis demonstrated that DMF promoted an anti-inflammatory/pro-reparative phenotype. By Seahorse analysis, DMF did not affect glycolysis in either macrophages or fibroblasts at day 3, but enhanced macrophage OXPHOS while impairing fibroblast OXPHOS. Our results indicate that DMF differentially affects macrophage and fibroblast metabolism, and promotes anti-inflammatory/pro-reparative actions. In conclusion, targeting cellular metabolism in the infarcted heart may be a promising therapeutic strategy.

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.

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