Intercellular Targetable Mechanistic Interface for Cardiac Fibrosis

Abstract

Cardiac fibrosis is a central pathological feature of heart failure and contributes to myocardial stiffening, impaired electrical conduction, and progressive ventricular dysfunction. Traditionally, fibrotic remodeling has been viewed as a fibroblast-driven process in which activated fibroblasts deposit excessive extracellular matrix following cardiac injury. However, emerging evidence indicates that fibrosis arises from coordinated interactions among multiple cardiac cell populations, including cardiomyocytes, endothelial cells, immune cells, pericytes, and fibroblasts. In this review, we discuss the role of cardiomyocytes and their interactions with other cell types in the heart in facilitating cardiac fibrosis. We discuss how interactions among cardiomyocytes, immune cells, endothelial cells, pericytes, and fibroblasts contribute to fibrotic remodeling in both ischemic and non-ischemic heart disease. Our signaling emphasis is on transforming growth factor-β (TGF-β)-mediated cardiac fibrosis in the context of cellular interplay. We posit that a better understanding of these integrated signaling networks may reveal new opportunities to prevent or reverse pathological cardiac fibrosis.

Keywords

Inflammation / Atrial / TGF-beta / SNRK / AMPK / Cardiac

Author Contributions

K.T.: Conceptualization, writing, and editing. R.R.: Writing and editing, funding acquisition, supervision, and resources.

Ethics Statement

Not applicable.

Informed Consent Statement

All studies references in this article have adhered to best practices for human and animal work, and were performed under approved protocols. Informed consent was obtained from all subjects involved in the referenced studies.

Data Availability Statement

All data references in this article are from the original papers that were cited. Data availability is included in the original papers.

Funding

R.R. and K.T. are partly funded through NIH grants R33 HL154254 and HL179583. R.R. and K.T. are also supported by program funds provided by Children’s Research Institute, and Department of Pediatrics, MCW.

Declaration of Competing Interest

Both authors in this manuscript do not have competing financial interest associated with the content in this manuscript.

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