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 isoformspecific 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.

Reverse Remodeling in Human Heart Failure after Cardiac Resynchronization Therapy Is Associated With Reduced RHO-Kinase Activation

“…The authors found that diffuse fibrosis and myocardial hypertrophy recovered to more normal levels during the first 2 months after aortic valve replacement, whereas focal fibrosis was comparatively permanent (Treibel et al, 2018). All of these myocardial damagerelated pathologic processes associated with reverse myocardial remodeling are promoted by ROCK activation (Shimizu and Liao, 2016;Dai et al, 2018;Yu et al, 2020). Our present findings of significant reverse remodeling 3 months after initiation of CRT in HFrEF are consistent with the role of ROCK activation in PBMCs as a marker of myocardial remodeling.…”

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

“…These enzymes belong to the AGC family of serine/threonine protein kinases and exist in two isoforms: ROCK1 (also named ROKβ or p160 ROCK ), encoded by gene ROCK1 on locus 18q11.1 and first identified in human platelet extracts [ 20 ] and ROCK2 (also named ROKα or Rho-kinase) encoded by the gene ROCK2 on locus 2p25.1 and isolated from rat brain extracts [ 21 ]. In mammals, both ROCK isoforms are ubiquitous but ROCK1 predominates in the kidney, spleen, liver, and ROCK2 in the brain and the heart [ 22 , 23 ]. This distribution suggests different functions, as described below [ 24 ].…”

“…Both isoforms of ROCK possess a similar tridimensional structure composed of three main regions: an N-terminal kinase domain, a Coiled-coil region containing the Rho-binding domain (RBD) and a C-terminal Pleckstrin homology domain (PHD), with an internal cysteine-rich zinc-finger domain [ 25 ]. The homology between ROCK1 and ROCK2 is equivalent to 65% along the entire protein but reaches over 90% in the kinase domain and they are almost identical in the ATP-binding site [ 23 , 24 , 25 ]. The kinase domain of ROCK is generally thought to be active, as indicated after cleavage by caspase-3 (for ROCK1) or granzyme B (for ROCK2), despite the slight catalytic activity of the enzyme.…”

Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's disease

“…Mice were treated with 2% DSS (in total 3 cycles) to induce chronic inflammation and, in the last cycle, were intraperitoneally injected with vehicle or ROCK1 inhibitor (15 mg/kg/day). 30 Nine weeks later, the chronic colitis was established. All surviving mice were sacrificed for subsequent analysis.…”

“…When RhoA-GTP activates ROCK1, various proteins are phosphorylated, such as myosin light chains, leading to decreased dissociated globular actin, actin gathering and the occurrence of stress fibres. 21,22 ROCK1 is regarded as a potential candidate for antifibrotic therapy. 22 A small molecule ROCK inhibitor showed antifibrotic effects in a chronic intestinal inflammation-induced fibrosis model.…”