Emerging therapeutic targets for cardiac arrhythmias: role of STAT3 in regulating cardiac fibroblast function

ABSTRACT

Introduction: Cardiac fibrosis contributes to the development of cardiovascular disease (CVD) and arrhythmia. Cardiac fibroblasts (CFs) are collagen-producing cells that regulate extracellular matrix (ECM) homeostasis. A complex signaling network has been defined linking environmental stress to changes in CF function and fibrosis. Signal Transducer and Activator of Transcription 3 (STAT3) has emerged as a critical integrator of pro-fibrotic signals in CFs downstream of several established signaling networks.

Areas covered: This article provides an overview of STAT3 function in CFs and its involvement in coordinating a vast web of intracellular pro-fibrotic signaling molecules and transcription factors. We highlight recent work elucidating a critical role for the fibroblast cytoskeleton in maintaining spatial and temporal control of STAT3-related signaling . Finally, we discuss potential opportunities and obstacles for therapeutic targeting of STAT3 to modulate cardiac fibrosis and arrhythmias. Relevant publications on the topic were identified through Pubmed.

Expert opinion: Therapeutic targeting of STAT3 for CVD and arrhythmias presents unique challenges and opportunities. Thus, it is critical to consider the multimodal and dynamic nature of STAT3 signaling. Going forward, it will be beneficial to consider ways to maintain balanced STAT3 function, rather than large-scale perturbations in STAT3 function.

KEYWORDS:

• Heart Failure
• fibrosis
• arrhythmia
• cardiac Fibroblasts
• stat3
• cytoskeleton
• spectrin

Article Highlights

• STAT3 signaling regulates cardiac fibrosis and susceptibility to cardiac arrhythmia.

• STAT3 resides downstream of several canonical pathways linked to cardiac fibroblast gene reprogramming.

• Spectrin-based cytoskeleton maintains spatial and temporal control of STAT3-related signaling in cardiac fibroblasts.

• STAT3 plays a multimodal role with its activation and inhibition both having beneficial effects in different settings.

• STAT3 may serve as an effective therapeutic target to modulate cardiac fibrosis and function in cardiac disease.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by National Institutes of Health grants R01-HL135096 and R01-HL134824 to TJH.