Background/Purpose Aberrant ROCK activity is implicated in the pathogenesis of many autoimmune and vascular disease states as ROCKs promote Th17 differentiation and vascular remodeling.  Increased ROCK activity has been demonstrated in temporal artery biopsies from GCA patients and ROCK is proposed to play a role in aortic aneurysm formation; however the role of ROCK in aortitis is unknown.  The aim of this study was to assess ROCK activity in aortic specimens from patients with GCA, TA and IA.

Methods All aortic aneurysm specimens with histopathologic evidence of aortitis diagnosed during a 1 year period at a single institution identified and corresponding medical record reviewed.  Patient history and ACR criteria were used to confirm diagnosis of GCA, TA, or IA.  Those with IgG4 disease were excluded.  Paraffin-embedded specimens were stained for Phospho-Ezrin/Radixin/Moesin (pERM), a surrogate of ROCK activity, using immunohistochemical stain.  Sections also stained for the un-phosphorylated ERM protein.  Inflammatory cells characterized using CD3/CD20 stain for T/B cells.  Aortic specimens without aortitis were also stained for ERM/pERM as controls. Stained slides reviewed by a pathologist blinded to clinical status. pERM intensity in the vasculature and inflammatory infiltrate was assessed. 

Results Of 12 eligible aortitis cases, 4 were in those with prior history of GCA, 3 had TA and 5 had IA. Expected demographic differences noted between groups.

In all compartments, pERM staining was notably more intense than ERM suggesting activation of ROCK.  All patients with aortitis had >50% of the inflammatory infiltrate staining positive for pERM, though TA patients had greater proportion of pERM negative inflammatory cells (CD 163+ histiocytes) than those with GCA or IA.  All patients, including 10 with non-inflammatory aortic aneurysms, had intense pERM staining of stromal cells in the adventitia and vasa vasorum, which was not affected by use of medications or co-morbidities known to influence ROCK (Table 1).   

Conclusion  The markedly more intense pERM staining compared to ERM in the vasculature and lymphocytic infiltrate from those with GCA, TA, and IA suggest the ROCK pathway is active in these disease states, though no major differences in stain intensity between groups was noted.  The pERM intensity in vessels of non-aortitis aneurysm controls supports the idea that ROCK may promote aneurysm development.  ROCK activation likely reflects a response to vascular damage and repair regardless of etiologic mechanism, though staining in the infiltrating lymphocytes suggests ROCK is also involved in the inflammatory response in aortitis.  These findings may ultimately have therapeutic implications, if confirmed in larger cohorts, especially in GCA as inhibition of ROCK may mitigate the initial inflammatory milieu as well as aneurysm formation, the most significant late disease manifestation.  

Table 1: Patient Demographics