Rho-Associated Coiled-Coil Research Articles

Response to Letters Regarding Article, “Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation”

We appreciate the comments by Settergren et al on differences in the patient population and response to lipid-lowering therapies between our 2 studies.1,2 We agree that our patient population had lower cardiovascular risks and higher on-treatment low-density lipoprotein cholesterol (LDL-C) levels. Thus, it is possible that LDL-C lowering alone may not be the overwhelming determinant of endothelial function as observed in our study. Furthermore, the lipid-lowering response to statin monotherapy and the combination of statin and ezetimibe may differ between white and Asian patients.3 Regardless of these ethnic and cardiovascular risk factor differences, the LDL reduction was similar between simvastatin 40 mg and simvastatin/ezetimibe 10 mg/10 mg in our study. However, endothelial function differed significantly between these 2 treatment groups (simvastatin 40 mg versus simvastatin/ezetimibe 10/10 mg: +32.1% versus −0.5%, P <0.01). Because of these contrasting results, we agree that there is a need for a larger-scale and perhaps multicenter study to further investigate whether changes in endothelial function with statin therapy are solely dependent on LDL-C lowering and, if so, whether they are affected by patient background and the degree of LDL-C lowering. From the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy/Thrombolysis in Myocardial Infarction 22 (PROVE-IT/TIMI 22) and the Treating to New Targets (TNT) trials, it is clear that a greater reduction in LDL-C with either a more potent statin, a higher dose of statin, or both leads to a greater reduction in cardiovascular events. …

Letter by Tershakovec et al Regarding Article, “Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation”

To the Editor: The article in Circulation by Liu et al1 claims that statin monotherapy provides greater “pleiotropic effects” than low-dose statin with ezetimibe due to the effects on Rho-kinase activity, which is postulated to play a role in flow-mediated dilation (FMD), a surrogate marker for endothelial function. We believe this article has significant limitations related to its design, presentation, and conclusions. Ezetimibe would not be expected to directly influence Rho-kinase activity, so the treatment group differences in Rho-kinase activity in this study are expected. However, the clinical significance of changes in Rho-kinase activity with respect to cardiovascular risk is entirely speculative. The utility of FMD assessment in clinical research remains unknown, compounded by the …

Letter by Westerink and Visseren Regarding Article, “Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation”

To the Editor: For daily clinical practice, it is important to know which lipid-lowering strategy for reaching recommended low-density lipoprotein cholesterol treatment goals is most effective in lowering cardiovascular risk: high-dose statin or low-dose statin in combination with inhibiting intestinal cholesterol uptake. Both strategies lead to a similar 40% to 50% low-density lipoprotein cholesterol reduction. To date, there are no prospective cohort studies with hard clinical end points addressing this issue. In their study, Liu et al1 show that low-risk patients randomized to simvastatin 40 mg had higher flow-mediated dilation (FMD) …

Clinical Summaries

Clinical Summaries

Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632.

Intrahepatic metastasis is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). Cell motility mediated by Rho- and p160 Rho-associated coiledcoil forming protein kinase (p160ROCK) signaling pathways has recently been shown to play a critical role in intrahepatic metastasis in human HCC. Furthermore, the stable introduction of dominant-negative p160ROCK into Li7 cells resulted in a reduced metastatic rate in mice with severe combined immunodeficiency (SCID). To investigate whether the specific p160ROCK inhibitor, Y-27632, could also inhibit intrahepatic metastasis, the effect of Y-27632 on the cell motility and intrahepatic metastasis of Li7 was investigated. Y-27632 markedly blocked actin reorganization and motility of Li7 cells mediated by lysophosphatidic acid (LPA). Y-27632 was administered continuously into the peritoneal cavity using a micro-osmotic pump, together with orthotopic implantation of Li7 cells into the liver of SCID mice. Phosphate-buffered saline (PBS) alone was administered as the control. The incidence of mice with metastatic nodules decreased in the Y-27632-treated group. The primary tumor volume at the site of injection was smaller in the Y-27632-treated group compared with the control group, but the difference was not statistically significant. Histologically, control tumors showed infiltrative growth into the sinusoidal area at the tumor boundary, whereas Y-27632-treated tumors showed expansive growth and low invasiveness. These findings confirm the importance of the Rho/p160ROCK signaling pathway in intrahepatic metastasis of human HCC, and indicate that Y-27632 may be useful for the prevention of intrahepatic metastasis of human HCC.