Editorial http://dx.doi.org/10.4070/kcj.2012.42.6.379 Print ISSN 1738-5520 • On-line ISSN 1738-5555 Korean Circulation Journal Rho-Associated Kinase 2 Polymorphism of Vasospastic Angina in Korean Population Chul Soo Park, MD Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Yeouido St. Mary’s Hospital, Seoul, Korea Refer to the page 406-413 periments, we can speculate that an increased activity of ROCKs can be one of the important pathophysiologic mechanisms of vaso- spastic angina, and fasudil, a ROCK inhibitor has exerted beneficial Rho-associated kinases (ROCKs), the immediate downstream effect on VA.4) targets of RhoA, are ubiquitously expressed serine-threonine pro- Rho-associated kinases could regulate other cellular functions tein kinases, which are involved in diverse cellular functions, includ- that are independent of their effects on the actin cytoskeleton. For ing smooth muscle contraction, actin cytoskeleton organization, cell examples, Rock inhibits insulin signaling, reduces cardiac hypertro- adhesion and motility, and gene expression. Recent studies have phy and involves an in tissue differentiation from adipocyte to myo- shown that ROCKs may play a pivotal role in cardiovascular diseases, cyte. such as vasospastic angina, ischemic stroke, and heart failure. In addition to ROCK’s effect on actin cytoskeleton system, inhibi- Rho-associated kinases are important regulators of cellular apop- tory effect on endothelial nitric oxide synthase (eNOS) activity can tosis, growth, metabolism, and migration via control of the actin cy- be another mechanism involved in the pathogenesis of vasospasm. toskeletal assembly and cell contraction.1) ROCKs phosphorylate var- Enothelium derived NO plays an important role in the regulation ious targets and mediate broad range of cellular responses that in- of vascular tone, inhibition of platelet aggregation, and the suppres- volve in actin cytoskeleton in response to GTPase-RhoA. ROCKs in- sion of smooth muscle cell proliferation. Increased bioavailability of crease myosin light chain (MLC) phosphorylation through phos- NO is, in part, dependent on eNOS activity. Although various condi- phorylating the myosin binding subunit on myosin light chain ph- tions and factors, such as laminar shear stress, oxygen tension, and osphatase (MLCP) and inhibition of MLCP.2) In addition, MLC is one transforming growth factor β-1, can regulate eNOS expression by of the major downstream target proteins of ROCKs. ROCK2 phosph- transcriptional level, eNOS expression can be regulated at the post- orylates Ser19 of MLC, the same residue that is phosphorylated by transcriptional level. Chronic hypoxia,5) tumor necrosis factor-α,6) th- MLC kinase. Thus, ROCK2 may increase cellular contractility via dual rombin,7) oxidized low density lipoprotein-cholesterol,8) and cellular effects on MLC kinase and MLCP. Indeed, ROCK2 can alter the sen- proliferation9)10) are known to decrease eNOS messenger ribonucleic sitivity of vascular smooth muscle cell (VSMC) contraction, in resp- acid (mRNA) stability. Chronic hypoxia and cellular proliferation are onse to the changes in Ca2+ concentration.3) Based on the above ex- known to activate RhoA and ROCKs,11) thus, RhoA/ROCK inversely regulates eNOS expression, through an alteration in the eNOS mRNA Chul Soo Park, MD, Division of Cardiology, Department of Correspondence: stability. The RhoA/ROCK pathway may also be important in the reg- Internal Medicine, College of Medicine, The Catholic University of Korea, Yeouido St. Mary’s Hospital, 62 Yeouido-dong, Yeongdeungpo-gu, Seoul ulation of eNOS activity. The regulation of eNOS activity can occur 150-713, Korea via eNOS phosphorylation. The phosphorylation of Ser1177 of eNOS Tel: 82-2-3779-1325, Fax: 82-2-3779-1374 leads to the rapid activation of eNOS by fluid shear stress, insulin, E-mail: [email protected] estrogen, bradykinin, and vascular endothelial growth factor.12)13) In- • The author has no financial conflicts of interest. terestingly, inhibition of RhoA or ROCKs lead to the rapid activation This is an Open Access article distributed under the terms of the Creative of PI3K/Akt and phosphorylation of eNOS,14)15) which suggests the Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, potential role of ROCKs in the regulation of eNOS activation, in ad- distribution, and reproduction in any medium, provided the original work dition to the eNOS expression. is properly cited. In the mammalian system, ROCKs consist of two isoforms, ROCK1 Copyright © 2012 The Korean Society of Cardiology 379 380 ROCK2 Polymorphism and Vasospastic Angina and ROCK2. ROCK1 and ROCK2 are ubiquitously expressed in mouse only 3.45% in the control group and 0% in the VA group and the tissues, from early embryonic development to adulthood. ROCK1 prevalent genetic haplotypes, consisting of more than 95% of mRNA is preferentially expressed in the lung, liver, spleen, kidney, study population, did not show any significant difference in haplo- and testis, whereas, ROCK2 mRNA is highly expressed in the heart type distribution between the VA and the control group, whereas, and brain.16)17) other studies regarding eNOS genetic polymorphism have reported In this issue of the journal, You et al.18) performed a novel study mutations having 25%21) to 50%20) of frequencies in VA population. to evaluate the relationship between ROCK2 genetic polymorphism In other words, the authors could not find high risk genetic muta- and VA in Korean the population. To my knowledge, this is the first tions or haplotypes, which can be a major determinant of the VA study regarding ROCK2 gene polymorphism in Korean population. pathogenesis. Therefore, we might speculate that other genetic al- As the authors described, VA is a multifactorial disease, which has terations or environmental factors are probably more closely relat- a diverse pathogenetic mechanisms, such as VSMC hypersensitivity, ed to VA than ROCK2 genetic polymorphism is, and the studies re- endothelial dysfunction, increased oxidative stress, and etc. In addi- garding other SNPs of ROCK2 gene might be required to understand tion, smoking and heavy alcohol drinking is considered to be im- the exact role of ROCK2 genetic polymorphism in VA patients. portant risk factors. VA is generally considered to be a benign cor- This study investigated the genotype difference between VA pa- onary artery disease, and most of the patients are treated well with tients and that of the normal controls. In the clinical perspective, calcium channel blocker and coronary vasodilator. However, some VA is not difficult to diagnose and the detection of high risk pa- patients have trouble in ameliorating chest pain and severe VA can tient is important. The investigation of genetic polymorphism, be- cause sudden cardiac death. Considering the function of ROCKs, al- tween refractory VA and usual VA, would be more useful because ready discovered in cellular and molecular researches, it could be most of the patients are treated well with the conventional coronary expected to give us substantial information to perform genetic study, vasodilatory drugs, but the refractory patients whose genotype is regarding Rho-ROCK pathway in VA patients. not favorable for VA might require additional therapy targeting ge- According to this study, the genotype prevalence of all five inter- netic alterations. esting SNPs (rs978906, rs2271621, rs2230774, rs1515219 and In spite of several limitations, this article suggested the associa- rs3771106) of ROCK 2, in the VA group, was not significantly differ- tion of genetic polymorphism of ROCK2 and VA in Korean popula- ent from that in the control group. In haplotype analysis, G-T-C-T-G tion which has never been reported before. More large population haplotype was found to be significantly more prevalent in the con- study including functional study is needed to clarify and approve trol group than in the VA group. These findings could have some cli- this hypothesis before clinical application. nical implications. First of all, there were already some reports19-21) regarding eNOS References polymorphism in coronary vasospasm. If this study result is com- 1. Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. bined with that of the previous genetic studies, the VA patients can Nat Rev Mol Cell Biol 2003;4:446-56. be treated based on each patient’s genotype. For example, the pa- 2. Somlyo AP, Somlyo AV. Signal transduction by G-proteins, rho-kinase tients who have ROCK2 gene alteration might be treated with ROCK and protein phosphatase to smooth muscle and non-muscle myosin inhibitor, such as fasudil, and patients, who have eNOS gene alter- II. J Physiol 2000;522(Pt 2):177-85. ation and decreased eNOS activity, might be treated well with l-ar- 3. Amano M, Ito M, Kimura K, et al. Phosphorylation and activation of ginine or nitrate. In a previous report, L-arginine improved symp- myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996; 271:20246-9. toms and quality of life in the patients with eNOS T-786C mutation Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. 20) 4. which was more frequently detected in VA than control group. Suppression of coronary artery spasm by the Rho-kinase inhibitor fa- However, the authors did not perform functional studies. There- sudil in patients with vasospastic angina. Circulation 2002;105:1545-7. fore, it remains uncertain how this G-T-C-T-G halotype prevents co- 5. Laufs U, Endres M, Stagliano N, et al. Neuroprotection mediated by ronary vasospasm. Testing vasodilatory responses to acetylcholine, changes in the endothelial actin cytoskeleton. J Clin Invest 2000;106: l-arginine or various coronary vasodilators in different genetic hap- 15-24. lotypes might be helpful to discriminate the function of ROCK2 gene 6. Yoshizumi M, Perrella MA, Burnett JC Jr, Lee ME. Tumor necrosis factor alteration. downregulates an endothelial nitric oxide synthase mRNA by shorten- ing its half-life.