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, 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, pro-fibrotic 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-crosstalk 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.

STAT1/3 and ERK1/2 Synergistically Regulate Cardiac Fibrosis Induced by High Glucose

“…Hyperglycemia-mediated proliferation of cardiac fibroblasts and synthesis of collagens are cooperatively regulated by many intracellular and extracellular factors [37]. In addition to the STAT pathway, HG can also promote the production of collagens via activation of ERK1/2 [15].…”

From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure

“…In addition, cross-talk between cardiomyocytes and other cardiac cell types (e.g. cardiac fibroblast) occurs that influences cardiac function and pathophysiology [9, 10]. In response to a pathological insult, factors including angiotensin II (Ang II), endothelin 1 (ET-1) and noradrenaline (NE) are released and bind to G q protein-coupled receptors (GPCR) which in turn activate multiple downstream effectors to stimulate hypertrophy.…”

Autonomic Dysfunction: A Driving Force for Myocardial Fibrosis in Young Duchenne Muscular Dystrophy Patients?

“…Secondly, disruptions in regulatory function and signaling pathways may occur secondary to the absence of dystrophin [9]. Hence, deficiency of dystrophin in cardiac myocytes, whether by physical absence or disruption of signaling, leaves cells exposed to stressful stimuli such as chemical, mechanical, neurohormonal, or inflammatory insults, thereby leading to cell death and fibrotic replacement [12]. Therefore, we hypothesized that autonomic dysfunction in DMD, manifested by abnormal HRV, will be associated with myocardial fibrosis and may in part be the driving force for the myocardial scar that develops in DMD.…”