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In the injured heart (right panel), the loss of cardiomyocytes induces an acute immune response, and leads to the activation of the tissue quiescent fibroblasts, and their differentiation into activated myofibroblasts.
In turn, these myofibroblasts deposit scar tissue that replaces the damaged myocardium, leading to reduced contractility, increased rigidity and adverse remodeling of the cardiac wall.
Mitigating this process will involve the coordinated induction of the following events: decreasing cardiomyocyte death, stimulating cardiomyocyte proliferation and angiogenesis, modulating the immune response, preventing fibroblasts activation and differentiation.
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In cardiomyocytes, CAM-6019 interact with its receptor, a-dystroglycan (a part of the dystroglycan complex), and leads to the release of YAP (yes-associated protein) to the nucleus and activation of ERK (extracellular signal-related kinase). This leads to cardiomyocyte proliferation and survival, increasing the amount of post injury myocardium (Bassat et al, Nature 2017, Baher et al, Circulation, 2020).
In cardiac fibroblasts, CAM-6019 interacts with its integrin receptors, and via a signaling pathway including FAK (focal adhesion kinase), AKT (Ak strain transforming protein, also known as protein kinase B) and ERK. CAM-6019 induces the expression of EGR1 (early growth response 1), a master regulatory transcription factor. This results in a transient cardiac fibroblast senescence, which is required for heart repair. Further, senescent cardiac fibroblasts secrete SASP (senescence associated secretory phenotype) factors, which affect ECM remodeling and other cell types (Sarig et al, Circulation, 2019, Zhang et al, Nature CV research, 2024).
In endothelial cells, CAM-6019 induces activation and formation of new blood vessels (angiogenesis), supporting the new and surviving myocardium (Baher et al, Circulation, 2020).
In immune cells (macrophages), CAM-6019 modulates the immune response (e.g. less recruitment of activated macrophages), leading to a pro-regenerative immune response in the injured heart.
Taken together, these CAM-6019 cellular processes result in reduced scar and improved cardiac function.
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Upper panels: cross section of injured hearts; scar is visualized by TTC staining, and is illustrated below by the red (healthy) and black (scar) representations. Scarring of the left anterior wall and septum is reduced in the CAM-6019 treated heart compared to control.
Lower panels: sections of myocardium from injured hearts, collected from the border zone around the infarct region; Interstitial fibrosis is visualized by Sirius Red staining. Fibrosis of the non-injured tissue is reduced ub the CAM-6019 treated heart compared to control.
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