A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation

Abstract

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT₂R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

Keywords: MMPs; atrial fibrillation; cardiac fibrosis; miRNAs; neurohormonal mechanisms.

Figure 1

TGF-β signalling pathway and Ang II effects via AT₁-R and AT₂-R receptors. Ang II—angiotensin II; AT₁R—angiotensin type I receptor; AT₂R—angiotensin type II receptor; CTGF—connective tissue growth factor; ECM—extracellular matrix; MAPK—mitogen-activated protein kinase; MMP—matrix metalloproteinase; NOX—nicotinamide adenine dinucleotide phosphate oxidase; PAI-1—plasminogen activator inhibitor 1; ROS—reactive oxygen species; Smad 2/3—Smad family member 2/3; TGF-β—transforming growth factor β; TGFβR1,-2,-3—transforming growth factor receptor β1,-2,-3.

Figure 2

CTGF as the central mediator of tissue remodelling and atrial fibrosis. ⟙ (red arrow) inhibition; LA—left atrium; Rac 1—Rac family small GTPase 1.

Figure 3

Modulation of signalling pathways by miRNAs in the pathogenesis of atrial fibrosis. ↑ up regulation of miR; ↓ down regulation of miR; ⟙ (red arrow) inhibition; → (green arrow) activation. miR—microRNA; β-MHC—β-myosin heavy chain; Sprouty 1—protein Sprouty homolog 1.

Figure 4

Possible association of atrial fibrillation with atrial remodelling, inflammation and oxidative stress. ⤏ modulation of the expression; → activation of the expression. AF—atrial fibrillation; CAD—coronary artery disease; HF—heart failure; HT—hypertension; PDGF—platelet-derived growth factor; RAAS—renin-angiotensin-aldosterone system; TIMP—tissue inhibitor of metalloproteinase.