Competitive signaling and cellular communications in myocardial infarction response

Abstract

Cell communication and competition pathways are malleable to Myocardial Infarction (MI). Key signals, transcriptive regulators, and metabolites associated with apoptotic responses such as Myc, mTOR, and p53 are important players in the myocardium. The individual state of cardiomyocytes, fibroblasts, and macrophages in the heart tissue are adaptable in times of stress. The overlapping communication pathways of Wnt/β-catenin, Notch, and c-Kit exhibit the involvement of important factors in cell competition in the myocardium. Depending on the effects of these pathways on genetic expression and signal amplification, the proliferative capacities of the previously stated cells that make up the myocardium, amplify or diminish. This creates a distinct classification of "fit" and "unfit" cells. Beyond straightforward traits, the intricate metabolite interactions between neighboring cells unveil a complex battle. Strategic manipulation of these pathways holds translational promise for rapid cardiac recovery post-trauma.

Keywords: Cardiac healing; Cardiac regeneration; Cell communication; Cell competition; Myocardial infarction.

Fig. 1

Dynamic Cross-Regulation Between Notch and Wnt/β-Catenin Pathways: The figure depicts two cells, both with Notch and Wnt receptors interacting with each other; cell-1 with Notch activated and cell-2 Wnt/β-Catenin initiated. Ligands from cell-2 attach to the Notch receptors on cell-1 to release the intracellular component of the Notch receptor (NCID). The NCID enters the nucleus to upregulate c-Myc activity and to induce the release of Wnt antagonists Notum1b and Wif1. These components block Wnt activation to its Frizzled receptor. In cell 2, the Wnt attachment to the Frizzled receptor is evident as the protein DVL phosphorylates β-Catenin to induce transcription to miR218. This ultimately differentiates and specializes the cell rather than continued cell growth as seen in cell 1

Fig. 2

c-Kit Receptor in Signal Cascades Governing Cellular Proliferation: Stem cell factors from neighboring stromal cells and fibroblasts bind the c-kit receptor in stress-induced conditions. Signal transducer, PIK3 activates mTORC2 or phosphorylate AKT to prime the mTORC1 signal pathway. Upon activation, Raptor, an extension of mTORC1, phosphorylates kinase S6K, which triggers hnRNPA to initiate c-Myc transcription. The availability of c-Myc determines the active or inactive state of tumor suppressor p53. p53’s expression accelerates cell proliferation and survival

Fig. 3

Interplay of Myc, mTOR, and p53 in Cellular Fitness Regulation: Growth factors such as IGF-1 latch onto cell-surface receptors to prime PIK3 where the PIK3 primarily targets mTORC2, making it phosphorylate kinases, AKT, and SGK1. The phosphorylation of these intermediates inhibits FOXOs in the nucleus, which usually act as tumor suppressors. FOXO arrest induces c-Myc transcription, thus supporting ribosomal gene expression and protein synthesis vital to cell cycle interphase. Additionally, AKT and SGK1 phosphorylation causes MDM2 to inhibit p53 tumor suppression, thereby increasing cell proliferative capacity. Meanwhile induced stress on the ER activates the role of mTORC1 in Lipid metabolism and structural development for the cell cycle