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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. [Display omitted] • 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 FROM AUTHOR]

Fibrotic scarring is tightly linked to the development of heart failure in patients with post-myocardial infarction (MI). Atypical chemokine receptor 4 (ACKR4) can eliminate chemokines, such as C–C chemokine ligand 21 (CCL21), which is independently associated with heart failure mortality. However, the role of ACKR4 in the heart during MI is unrevealed. This study aimed to determine whether ACKR4 modulates cardiac remodeling following MI and to illuminate the potential molecular mechanisms. The expression of ACKR4 was upregulated in the border/infarct area, and ACKR4 was predominantly expressed in cardiac fibroblasts (CFs). Knockout of ACKR4 protected against adverse ventricular remodeling in mice post-MI. These protective effects of ACKR4 deficiency were independent of dendritic cell immune response but could be attributed to downregulated CF-derived IL-6, affecting CF proliferation and endothelial cell (EC) functions, which consequently inhibited cardiac fibrosis. ACKR4 promoted IL-6 generation and proliferation of CFs. Besides, ACKR4 induced endothelial-to-mesenchymal transition (EndMT) in ECs through IL-6 paracrine effect. The p38 MAPK/NF-κB signaling pathway was involved in ACKR4 facilitated IL-6 generation. Moreover, ACKR4 overexpression in vivo via AAV9 carrying a periostin promoter aggravated heart functional impairment post-MI, which was abolished by IL-6 neutralizing antibody. Therefore, our study established a novel link between ACKR4 and IL-6 post-MI, indicating that ACKR4 may be a novel therapeutic target to ameliorate cardiac remodeling. • ACKR4 expression is upregulated in infarcted heart and exclusively detected in CFs. • ACKR4 deletion alleviates cardiac remodeling after MI. • The cardioprotective effect induced by ACKR4 deletion is DCs-trafficking independent. • Knockout of ACKR4 reduces proliferation, IL-6 generation of CFs in vitro. • Overexpression of ACKR4 aggravates cardiac dysfunction after MI via IL-6 in vivo. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis after myocardial infarction (MI) is mainly associated with cardiac fibroblasts and its differentiation is the key pathological process. However, the cellular mechanism of fibroblast-to-myofibroblast conversion has not been clarified and a deeper mechanistic understanding is needed. We found that miR-574–5p was up-regulated in TGF-β-induced myofibroblast differentiation. Silencing transiently miR-574–5p in HCFs, we found that suppression of miR-574–5p decreased myofibroblasts differentiation as validated by expression levels of fibrosis related genes, EDU imaging assay, wound healing assay and transwell assays. Conversely, overexpression of miR-574–5p displayed opposite results. ARID3A was verified as a direct target gene of miR-574–5p and decreased level of ARID3A forced fibroblast-to-myofibroblast differentiation of TGF-β-induced HCFs. Our data suggests that miR-574–5p plays a pivotal role in human cardiac fibroblasts (HCFs) myofibroblast differentiation and demonstrates that miR-574–5p and arid3a may be a novel therapeutic target for cardiac fibrosis. • We first demonstrated that miR-574–5p promotes the differentiation of HCFs. • ARID3A is the direct target gene of miR-574–5p. • Suppression of ARID3A recovered the anti-fibrotic response of miR-574–5p knockdown on TGF-β stimulation. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis (CF), a repairing process following myocardial infarction (MI), is characterized by abnormal proliferation of cardiac fibroblasts and excessive deposition of extracellular matrix (ECM) resulting in inevitable resultant heart failure. TGF-β (transforming growth factor-β)/ALK5 (Activin receptor-like kinase 5)/Smad2/3/4 pathways have been reported to be involved in the process. Recent studies have implicated both activin and its specific downstream component ALK4 in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 is upregulated in the pressure-overloaded heart and its partial inhibition attenuated the pressure overload-induced CF and cardiac dysfunction. However, the role of ALK4 in the pathogenesis of MI-induced CF, which is usually more severe than that induced by pressure-overload, remains unknown. Here we report: 1) In a wild-type mouse model of MI, ALK4 upregulation was restricted in the fibroblasts of the infarct border zone; 2) In contrast, ALK4+/- mice with a haplodeficiency of ALK4 gene, showed a significantly attenuated CF in the border zone, with a smaller scar size, a preserved cardiac function and an improved survival rate post-MI; 3) Similarly to pressure-overloaded heart, these beneficial effects might be through a partial inactivation of the Smad3/4 pathway but not MAPK cascades; 4) The apoptotic rate of the cardiomyocytes were indistinguishable in the border zone of the wild-type control and ALK4+/- mice; 5) Cardiac fibroblasts isolated from ALK4+/- mice showed reduced migration, proliferation and ECM synthesis in response to hypoxia. These results indicate that partial inhibition of ALK4 may reduce MI-induced CF, suggesting ALK4 as a novel target for inhibition of unfavorable CF and for preservation of LV systolic function induced by not only pressure-overload but also MI. [ABSTRACT FROM AUTHOR]

The majority of cardiac fibroblasts in a mature mammalian heart are derived from the epicardium during prenatal development and reactivate developmental programs during the progression of fibrotic disease. In addition, epicardial activation, proliferation, and fibrosis occur with ischemic, but not hypertensive injury. Here we review cellular and molecular mechanisms that control epicardium-derived cell lineages during development and disease with a focus on cardiac fibroblasts. This article is part of a special issue entitled “Fibrosis and Myocardial Remodeling”. [ABSTRACT FROM AUTHOR]