Targeting Rho-associated coiled-coil forming protein kinase (ROCK) in cardiovascular fibrosis and stiffening

ABSTRACT

Introduction: Pathological cardiac fibrosis, through excessive extracellular matrix protein deposition from fibroblasts and pro-fibrotic immune responses and vascular stiffening is associated with most forms of cardiovascular disease. Pathological cardiac fibrosis and stiffening can lead to heart failure and arrythmias and vascular stiffening may lead to hypertension. ROCK, a serine/threonine kinase downstream of the Rho-family of GTPases, may regulate many pro-fibrotic and pro-stiffening signaling pathways in numerous cell types.

Areas covered: This article outlines the molecular mechanisms by which ROCK in fibroblasts, T helper cells, endothelial cells, vascular smooth muscle cells, and macrophages mediate fibrosis and stiffening. We speculate on how ROCK could be targeted to inhibit cardiovascular fibrosis and stiffening.

Expert opinion: Critical gaps in knowledge must be addressed if ROCK inhibitors are to be used in the clinic. Numerous studies indicate that each ROCK isoform may play differential roles in regulating fibrosis and may have opposing roles in specific tissues. Future work needs to highlight the isoform- and tissue-specific contributions of ROCK in fibrosis, and how isoform-specific ROCK inhibitors in murine models and in clinical trials affect the pathophysiology of cardiac fibrosis and stiffening. This could progress knowledge regarding new treatments for heart failure, arrythmias and hypertension and the repair processes after myocardial infarction.

KEYWORDS:

• Rho
• ROCK
• fibrosis
• heart failure
• vascular stiffness
• arrhythmias
• myocardial infarction

Article highlights

• ROCK plays a key role in the regulation of fibrosis and stiffening in hypertension, heart failure, cardiomyopathies, arrythmias, and recovery after myocardial infarction

• ROCK activates pro-fibrotic genes in fibroblasts and myofibroblasts through MRTF/SRF, YAP/TAZ/TEAD, and TGF-β signaling

• ROCK plays an important role in the release of both pro-fibrotic and anti-fibrotic cytokines from T_h cells and may also play a role in macrophage polarization

• ROCK regulates endothelial function, including NO production and EndMT, to cause cardiac fibrosis and stiffening

• ROCK governs VSMC-ECM dynamics, VSMC phenotype switching, and vascular tone

• Future clinical trials on the use of ROCK inhibitors to decrease cardiac fibrosis or improve vascular stiffening are required to fully assess ROCK as a therapeutic target.

Declaration of interest

JE Blair has received research and equipment grants from Abbott and Phillips Healthcare. The authors have no other 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

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The work of the authors is funded by American Heart Association and the National Institutes of Health, National Heart, Lung and Blood Institute, USA.