Beyond cardiac fibroblasts: research advances on understanding and targeting intercellular communication networks in cardiac fibrosis

Figure 1. (A) Cardiomyocytes, macrophages, and endothelial cells produce transforming growth factor-β (TGF-β). (B) Immune cells release inflammatory cytokines, interleukin (IL)-1β and IL-6, which recruit and polarize macrophages. These macrophages, in turn, stimulate fibroblast proliferation and collagen synthesis. (C) Following a myocardial infarction, activated TGF-β engages cardiac fibroblasts via paracrine signaling, converting them into myofibroblasts and enhancing the synthesis and deposition of extracellular matrix (ECM) proteins. Additionally, TGF-β creates a positive feedback loop that continually amplifies fibrotic signaling.

Figure 2. (A) In the early stages of fibrosis, increased stiffness of the extracellular matrix (ECM) converts mechanical signals into intracellular chemical signals via integrins αvβ3 and α5β1. This conversion activates the YAP/TAZ pathway, resulting in fibroblast activation and heightened ECM deposition. (B) In a mouse model of pressure-overload-induced hypertrophic cardiomyopathy, fibroblast-secreted protein PTN initiates inflammatory responses and fibrosis by binding to the SDC4 receptor on macrophages.

Figure 3. (A) Necrotic apoptosis in cardiomyocytes results in the release of significant amounts of DAMPs, which activate the inflammatory response in adjacent macrophages and subsequently drive fibrosis. (B) Under stress conditions, cardiomyocytes release DAMPs, such as adenosine triphosphate (ATP), which play a crucial role in intercellular communication. (C) ATP interacts with P2X and P2Y purinergic receptors, regulating calcium ions, growth factors, cytokines, and nitric oxide through both autocrine and paracrine mechanisms. (D) The cardiac remodeling process encompasses hypertension, fibrosis, and myocardial hypertrophy.

Figure 4. (A) Isoproterenol (ISO) induces inflammation in white adipose tissue (WAT), which leads to the secretion of galectin-3. This secretion, in turn, activates cardiac fibroblasts and promotes cardiac remodeling. (B) A decrease in renal perfusion pressure activates the β-adrenergic receptors of the sympathetic nervous system, resulting in renin release and subsequent activation of the RAAS system. This process encourages myocardial hypertrophy and fibrosis through the actions of angiotensin II (AT-II) and aldosterone.