CVD and COVID-19: Emerging Roles of Cardiac Fibroblasts and Myofibroblasts

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide. Current data suggest that patients with cardiovascular diseases experience more serious complications with coronavirus disease-19 (COVID-19) than those without CVD. In addition, severe COVID-19 appears to cause acute cardiac injury, as well as long-term adverse remodeling of heart tissue. Cardiac fibroblasts and myofibroblasts, being crucial in response to injury, may play a pivotal role in both contributing to and healing COVID-19-induced cardiac injury. The role of cardiac myofibroblasts in cardiac fibrosis has been well-established in the literature for decades. However, with the emergence of the novel coronavirus SARS-CoV-2, new cardiac complications are arising. Bursts of inflammatory cytokines and upregulation of TGF-β1 and angiotensin (AngII) are common in severe COVID-19 patients. Cytokines, TGF-β1, and Ang II can induce cardiac fibroblast differentiation, potentially leading to fibrosis. This review details the key information concerning the role of cardiac myofibroblasts in CVD and COVID-19 complications. Additionally, new factors including controlling ACE2 expression and microRNA regulation are explored as promising treatments for both COVID-19 and CVD. Further understanding of this topic may provide insight into the long-term cardiac manifestations of the COVID-19 pandemic and ways to mitigate its negative effects.

Keywords: COVID-19; TGF-β1; fibroblast; fibrosis; myofibroblast.

Figure 1

Schematic depicting fibroblast to myofibroblast differentiation. Transforming growth factor-beta 1 (TGF-β1) is the most common pathway involved in the differentiation of fibroblasts into myofibroblasts. Resident fibroblasts, endothelial cells, and circulating hematopoietic cells may have the ability to become myofibroblasts via TGF-β1-induced pathways, granulocyte colony-stimulating factor (G-CSF), and endothelial-to-mesenchymal transition (EndMT). Progenitor stem cells and pericytes are also speculated to contribute to the myofibroblast population. Once myofibroblasts are differentiated, they produce more collagen and various pro remodeling factors required for healing. The expression of these factors at the site of injury promotes repair and remodeling of the injured myocardium. Usually after repair, myofibroblasts undergo apoptosis, decreasing the amount of collagen and pro remodeling factors expressed. When myofibroblasts fail to undergo apoptosis, more collagen and pro remodeling factors are expressed.

Figure 2

Schematic of SARS-CoV-2 viral entry via ACE2 receptor. SARS-CoV-2 enters the body by first binding to ACE2 receptors by the S protein. ACE2 is responsible for generating Ang-(1–7) from Ang II and acts mainly to reduce blood pressure. This binding can block the ACE2 receptor and reduce ACE2 activity, thereby significantly increasing Ang II levels and drastically decreasing Ang-(1–7) levels. Ang-(1–7) serves as anti-inflammatory, antifibrotic, antioxidative, and antiapoptotic. Ang II increases hypertension and other associated factors such as inflammation, fibrosis, oxidation, and apoptosis.