Gene Expression in Fibroblasts and Fibrosis

Abstract

Abstract-Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling. This review addresses the functional role played by cardiac fibroblasts and the molecular mechanisms that govern their activity during cardiac hypertrophy and remodeling. A particular focus is the recent progress toward our understanding of the transcriptional regulatory mechanisms involved. Key Words: transcription Ⅲ fibrosis Ⅲ myofibroblast Ⅲ cardiac remodeling R egardless of the origin, injury to the heart evokes a diverse and complex array of cellular responses involving both cardiomyocytes and nonmuscle cells that initiate and sustain a process of structural remodeling of the myocardium. 1 The importance of the structural remodeling has been addressed in randomized clinical trials. 2 For example, angiotensin-converting enzyme (ACE) inhibitors, which may delay and, in some cases, reverse cardiac remodeling, have proven to have a beneficial effect on morbidity and mortality in heart failure. Thus, remodeling is now generally accepted as a key determinant of the clinical course of heart failure. 2 Cardiac remodeling is manifested clinically as changes in the size, shape, and function of the heart. 2 Histopathologically, it is characterized by a structural rearrangement of components of the normal chamber wall that involves cardiomyocyte hypertrophy, cardiac fibroblast proliferation, fibrosis, and cell death. 3 Fibrosis, which is a disproportionate accumulation of fibrillar collagen, is an integral feature of the remodeling characteristic of the failing heart. Accumulation of type I collagen, the main fibrillar collagen found in cardiac fibrosis, stiffens the ventricles and impedes both contraction and relaxation. 4 Fibrosis can also impair the electrical coupling of cardiomyocytes by separating myocytes with extracellular matrix (ECM) proteins. 3 Furthermore, fibrosis results in reduced capillary density and an increased oxygen diffusion distance that can lead to hypoxia of myocytes. 5 Thus, fibrosis profoundly affects myocyte metabolism and performance and ultimately ventricular function. 6 In the myocardium, ECM proteins are mainly produced by fibroblasts that also produce matrix metalloproteinases Original received August 19, 2002; revision received October 30, 2002; accepted October 30, 2002. From the Departments of Cardiovascular Medicine (I.M., T.S., R.N.) and Clinical Bioinformatics (I.M., R.N.), University of Tokyo, Tokyo, Japan. Correspondence to Ichiro Manabe, MD, PhD,...

Interference with ERK Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

“…5C). This observation essentially excludes the possibility that up-regulation of ERK Thr188 phosphorylation in myocardial biopsies may originate from increased numbers or activation of cardiac fibroblasts attributable to increased interstitial fibrosis (42). Further clinical studies should aim to delineate whether these differences in ERK Thr188 phosphorylation are simply attributable to the mechanical differences (gradient) or whether the two forms are different clinical entities.…”

Fibroblasts modulate cardiomyocyte excitability: implications for cardiac gene therapy

“…4 A number of biological functions have been attributed to these fibroblasts, including cardiac remodelling and hypertrophy. 5 An electrophysiological function for fibroblasts in the myocardium on the other hand, although likely to exist, has not been elucidated. 6,7 In primary culture, fibroblasts have been reported to form gap junctions with cardiomyocytes and to conduct electrical impulse between cardiomyocytes.…”

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

“…In our opinion, this effect of ADAM23 on cardiac fibrosis is possibly secondary to its alleviation on cardiac hypertrophy. Cardiac hypertrophy and fibrosis would affect each other during heart failure 26. On the other hand, ADAM23 could directly affect the pathogenesis of fibrosis through the same downstream targets FAK, as is in regulating cardiac hypertrophy.…”