Cardiac intercellular communication: are myocytes and fibroblasts fair-weather friends?

Abstract

The cardiac fibroblast (CF) has historically been thought of as a quiescent cell of the heart, passively maintaining the extracellular environment for the cardiomyocytes (CM), the functional cardiac cell type. The increasingly appreciated role of the CF, however, extends well beyond matrix production, governing many aspects of cardiac function including cardiac electrophysiology and contractility. Importantly, its contributions to cardiac pathophysiology and pathologic remodeling have created a shift in the field's focus from the CM to the CF as a therapeutic target in the treatment of cardiac diseases. In response to cardiac injury, the CF undergoes a pathologic phenotypic transition into a myofibroblast, characterized by contractile smooth muscle proteins and upregulation of collagens, matrix proteins, and adhesion molecules. Further, the myofibroblast upregulates expression and secretion of a variety of pro-inflammatory, profibrotic mediators, including cytokines, chemokines, and growth factors. These mediators act in both an autocrine fashion to further activate CFs, as well as in a paracrine manner on both CMs and circulating inflammatory cells to induce myocyte dysfunction and chronic inflammation, respectively. Together, cell-specific cytokine-induced effects exacerbate pathologic remodeling and progression to HF. A better understanding of this dynamic intercellular communication will lead to novel targets for the attenuation of cardiac remodeling. Current strategies aimed at targeting cytokines have been largely unsuccessful in clinical trials, lending insights into ways that such intercellular cross talk can be more effectively attenuated. This review will summarize the current knowledge regarding CF functions in the heart and will discuss the regulation and signaling behind CF-mediated cytokine production and function. We will then highlight clinical trials that have exploited cytokine cross talk in the treatment of heart failure and provide novel strategies currently under investigation that may more effectively target pathologic CF-CM communication for the treatment of cardiac disease. This review explores novel mechanisms to directly attenuate heart failure progression through inhibition of signaling downstream of pro-inflammatory cytokines that are elevated after cardiac injury.

Figure 1. Pathologic Cardiac Intercellular Communication

In response to various chemical, mechanical, and ischemic stressors, the cardiac fibroblast (CF) undergoes a phenotypic transition to a myofibroblast, releasing a variety of growth factors, chemokines and cytokines that act both in an autocrine and paracrine fashion. Stimulation of CF results in a positive feedback loop to further enhance their activation, collagen deposition, and cytokine release, resulting in fibrosis and chronic inflammation. Cytokine effects on cardiomyocytes (CM) leads to pathologic effects including hypertrophy, apoptosis, and impaired contractile responses. Myocardial-generated cytokines also act on circulating inflammatory cells, such as monocytes, to enhance their activation and migration into cardiac tissue for wound healing and repair.

Figure 2. A Model for Pathologic Cardiac PAR-1 Receptor Transactivation

Adrenergic stimulation of the cardiac fibroblast (CF) via the β-AR leads to the production and release of MMP-13, which can, in a thrombin-independent manner, cleave PAR-1 receptors both on the CF and cardiomyocytes (CM) at a site distinct from thrombin cleavage. MMP-13-mediated PAR-1 activation results in ERK1/2-mediated CF and CM dysfunction. PAR-1-specific antagonism with SCH79797 attenuated the effects of MMP-13. Further, PAR-1 genetic ablation or MMP-13 inhibition with WAY170523 resulted in preserved cardiac function in response to chronic Isoproterenol infusion in wild-type mice, suggesting CF-CM receptor transactivation pathways may be novel therapeutic targets in the response to cardiac injury.