Statins inhibit Rho kinase activity in patients with atherosclerosis.
BACKGROUND
In addition to inhibiting cholesterol synthesis, statins (HMG-CoA reductase inhibitors) decrease the formation of isoprenoid intermediates required for the activation of key signaling pathways, including Rho/Rho kinase (ROCK). In experimental settings, statins inhibit ROCK and reverse vascular dysfunctions in atherosclerosis, independent of cholesterol reduction. It is not known whether statins inhibit ROCK activity in humans with atherosclerosis.


METHODS
We investigated 35 patients with stable atherosclerosis in a randomized, double-blind study comparing treatment with high-dose (80mg/d) or low-dose (10mg/d) atorvastatin to placebo for 28 days. Blood samples for leukocyte ROCK activity, fasting lipids, and high-sensitivity C-reactive protein (hs-CRP) were obtained on days 0, 7, 14, and 28 after randomization and change over time with the two statin treatments relative to placebo was examined.


RESULTS
Atorvastatin 80mg/d reduced ROCK activity (p=0.002 vs. placebo). This decline was rapid and significant within 2 weeks of treatment. The inhibition of ROCK by atorvastatin (80mg/d) remained significant even after controlling for changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides (p=0.01). Furthermore, there was no correlation between changes in ROCK activity and changes in LDL-C (r=0.2, p=0.25) or triglycerides (r=0.1, p=0.55). There was a modest correlation between ROCK inhibition and change in hs-CRP among patients randomized to atorvastatin 80mg/d (r=0.6, p=0.07).


CONCLUSIONS
These first-in-man findings demonstrate that high-dose atorvastatin rapidly inhibits the pro-atherogenic Rho/ROCK pathway, independent of cholesterol reduction. This inhibition may contribute to the clinical benefits of statins. Rho/ROCK may provide a useful therapeutic target in patients with atherosclerosis.
Nohria
Anju
A
Brigham and Women's Hospital, Boston, MA, USA.
Prsic
Adnan
A
Liu
Ping-Yen
PY
Okamoto
Ryuji
R
Creager
Mark A
MA
Selwyn
Andrew
A
Liao
James K
JK
Ganz
Peter
P
D000368:Aged; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology; D000069059:Atorvastatin; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011758:Pyrroles / Q000627:therapeutic use; D015398:Signal Transduction; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010919:Placebos; D011758:Pyrroles; D002097:C-Reactive Protein; D002784:Cholesterol; D000069059:Atorvastatin; D054460:rho-Associated Kinases