The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

Abstract

Cardiac fibroblasts (CF) play a pivotal role in the repair and remodeling of the heart that occurs following myocardial infarction (MI). The transition through the inflammatory, granulation and maturation phases of infarct healing is driven by cellular responses to local levels of cytokines, chemokines and growth factors that fluctuate in a temporal and spatial manner. In the acute inflammatory phase early after MI, CF contribute to the inflammatory milieu through increased secretion of proinflammatory cytokines and chemokines, and they promote extracellular matrix (ECM) degradation by increasing matrix metalloproteinase (MMP) expression and activity. In the granulation phase, CF migrate into the infarct zone, proliferate and produce MMPs and pro-angiogenic molecules to facilitate revascularization.Fibroblasts also undergo a phenotypic change to become myofibroblasts. In the maturation phase, inflammation is reduced by anti-inflammatory cytokines, and increased levels of profibrotic stimuli induce myofibroblasts to synthesize new ECM to form a scar. The scar is contracted through the mechanical force generated by myofibroblasts, preventing cardiac dilation. In this review we discuss the transition from myocardial inflammation to fibrosis with particular focus on how CF respond to alterations in proinflammatory and profibrotic signals. By furthering our understanding of these events, it is hoped that new therapeutic interventions will be developed that selectively reduce adverse myocardial remodeling post-MI, whilst sparing essential repair mechanisms.

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

“…6,7 Differentiation of the fibroblast to a myofibroblast phenotype is postulated to be as a consequence of excess fibrogenic pro-inflammatory cytokines frequently mediated by macrophage infiltration and oxidative stress. 8,9 Remodelling of excess ECM once deposited in the fibrotic process can occur as a result of expression of matrix metalloproteinases (MMPs) and their inhibitors [tissue inhibitors of matrix metalloproteinases (TIMPs)] with these changes leading to stiffening of the ECM, functional alterations that cause an increase in mechanical stress, cardiac hypertrophy and ultimately cardiac failure. 6,7,9,10 Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis Pre-clinical and clinical studies have identified cardioprotective effects of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 receptor (GLP-1R) agonists suggesting that these agents may have a role in modulation of the cardiac fibrosis phenotype.…”

A TRP to cardiac fibroblast differentiation

“…[1][2][3] Cardiac fibroblasts (CF) are the predominant cell types that secrete extracellular matrix (ECM) and help maintain the structural integrity of the heart. 4 CFs proliferate, migrate and differentiate to myofibroblasts during cardiac remodeling in disease states such as myocardial infarction (MI), atrial fibrillation (AF), and pressure overload-induced hypertrophy. [4][5][6][7] Myofibroblasts are hypersecretory, highly contractile and deposit excessive ECM proteins resulting in cardiac fibrosis that eventually form the scar.…”

“…4 CFs proliferate, migrate and differentiate to myofibroblasts during cardiac remodeling in disease states such as myocardial infarction (MI), atrial fibrillation (AF), and pressure overload-induced hypertrophy. [4][5][6][7] Myofibroblasts are hypersecretory, highly contractile and deposit excessive ECM proteins resulting in cardiac fibrosis that eventually form the scar. However, uncontrolled production of ECM proteins by prolonged survival of myofibroblasts can lead to pathological fibrosis.…”

Interleukin-23 Deficiency Leads to Impaired Wound Healing and Adverse Prognosis After Myocardial Infarction

“…34 We identified IFN-γ as the main coordinating cytokine in our model. Stimulation of cardiac fibroblasts with IFN-γ led to a significant downregulation of α-SMA, collagen I and III.…”