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Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities
- Source :
- Molecular Aspects of Medicine. 65:70-99
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Cardiac fibrosis is a common pathophysiologic companion of most myocardial diseases, and is associated with systolic and diastolic dysfunction, arrhythmogenesis, and adverse outcome. Because the adult mammalian heart has negligible regenerative capacity, death of a large number of cardiomyocytes results in reparative fibrosis, a process that is critical for preservation of the structural integrity of the infarcted ventricle. On the other hand, pathophysiologic stimuli, such as pressure overload, volume overload, metabolic dysfunction, and aging may cause interstitial and perivascular fibrosis in the absence of infarction. Activated myofibroblasts are the main effector cells in cardiac fibrosis; their expansion following myocardial injury is primarily driven through activation of resident interstitial cell populations. Several other cell types, including cardiomyocytes, endothelial cells, pericytes, macrophages, lymphocytes and mast cells may contribute to the fibrotic process, by producing proteases that participate in matrix metabolism, by secreting fibrogenic mediators and matricellular proteins, or by exerting contact-dependent actions on fibroblast phenotype. The mechanisms of induction of fibrogenic signals are dependent on the type of primary myocardial injury. Activation of neurohumoral pathways stimulates fibroblasts both directly, and through effects on immune cell populations. Cytokines and growth factors, such as Tumor Necrosis Factor-α, Interleukin (IL)-1, IL-10, chemokines, members of the Transforming Growth Factor-β family, IL-11, and Platelet-Derived Growth Factors are secreted in the cardiac interstitium and play distinct roles in activating specific aspects of the fibrotic response. Secreted fibrogenic mediators and matricellular proteins bind to cell surface receptors in fibroblasts, such as cytokine receptors, integrins, syndecans and CD44, and transduce intracellular signaling cascades that regulate genes involved in synthesis, processing and metabolism of the extracellular matrix. Endogenous pathways involved in negative regulation of fibrosis are critical for cardiac repair and may protect the myocardium from excessive fibrogenic responses. Due to the reparative nature of many forms of cardiac fibrosis, targeting fibrotic remodeling following myocardial injury poses major challenges. Development of effective therapies will require careful dissection of the cell biological mechanisms, study of the functional consequences of fibrotic changes on the myocardium, and identification of heart failure patient subsets with overactive fibrotic responses.
- Subjects :
- 0301 basic medicine
Cell type
Cardiac fibrosis
medicine.medical_treatment
Clinical Biochemistry
Biochemistry
Interstitial cell
Epigenesis, Genetic
03 medical and health sciences
0302 clinical medicine
Fibrosis
medicine
Animals
Humans
Macrophage
Myofibroblasts
Molecular Biology
Pressure overload
Ventricular Remodeling
business.industry
General Medicine
Fibroblasts
Endomyocardial Fibrosis
medicine.disease
Extracellular Matrix
Cell biology
030104 developmental biology
Cytokine
Cellular Microenvironment
Gene Expression Regulation
030220 oncology & carcinogenesis
Molecular Medicine
Tumor necrosis factor alpha
Disease Susceptibility
business
Biomarkers
Signal Transduction
Subjects
Details
- ISSN :
- 00982997
- Volume :
- 65
- Database :
- OpenAIRE
- Journal :
- Molecular Aspects of Medicine
- Accession number :
- edsair.doi.dedup.....0555159351049c6fb8c38364a8db7788