Related Experiment Videos
Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts
Insights
Cardiac fibroblasts produce heart
Area of Science:
- Cardiovascular biology
- Cellular and molecular medicine
Background:
- Cardiac fibroblasts are key to heart's extracellular matrix (ECM).
- Abnormal fibroblast activity and collagen deposition in hypertension and myocardial infarction impair heart function.
- Several factors influence fibroblast growth and collagen production.
Purpose of the Study:
- To investigate the role of Angiotensin II in cardiac fibroblast regulation.
- To elucidate the signaling pathways activated by Angiotensin II in cardiac fibroblasts.
- To understand how these pathways contribute to cardiac remodeling.
Main Methods:
- Review of existing literature on cardiac fibroblast function and ECM regulation.
- Analysis of signaling pathways activated by Angiotensin II through AT1 receptors.
- Examination of cellular responses including growth and protein synthesis.
Main Results:
- Angiotensin II, aldosterone, and endothelins drive ECM remodeling in hypertension.
- Growth factors like TGF-beta 1 and PDGF stimulate collagen synthesis and mitogenesis.
- Angiotensin II, via AT1 receptors, activates multiple signaling cascades (e.g., PLC-beta, PKC, MAPKs) leading to fibroblast hyperproliferation and increased ECM protein synthesis.
Conclusions:
- Angiotensin II is a major factor in cardiac fibroplasia and ECM synthesis in vivo.
- Cardiac fibroblasts' response to Angiotensin II involves complex signaling crosstalk.
- Understanding these pathways is crucial for targeting cardiac remodeling in cardiovascular diseases.
Abstract:
Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.