Rho Kinaz ve Kardiyovasküler Hastalıklar

Year 2010, Volume: 3 Issue: 2, - , 01.06.2010

A. Nihal Sarı Seyhan Şahan Fırat Bahar Tunçtan

Abstract

Abstract Rho Kinase and Cardiovascular Diseases Arterial diseases such as arteriosclerosis and hypertension are characterized by proliferation and hypertrophy of smooth muscle cells. The common feature of these diseases is endothelial dysfunction, which regulates the growth and tone of vascular smooth muscle cells. Inflammatory mediators like tumor necrosis factor alfa, interleukin-1β cause accumulation and adhesion of monocytes to the vessel wall by up-regulation of monocyte chemotactic peptide-1 and adhesion molecules such as vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, as well as migration, proliferation of vascular smooth muscle cells, and vessel obstruction. Rho kinase, sub-effector of small G protein Rho has two isoforms named as ROKα/ROCK II and ROKβ/ROCK I. ROCK mediates various cellular functions such as smooth muscle contraction, actin cytoskeleton formation, cell adhesion and motility, proliferation, cytokinesis, and gene expression that play a role in pathogenesis of cardiovascular diseases. Preclinical and clinical studies with selective ROCK inhibitors, fasudil and Y-27632, have shown that ROCK has an important role in the pathogenesis of cardiovascular diseases such as coronary vasospasm, hypertension, pulmonary hypertension, angina, myocardial infarction, stroke and heart failure. Also, beneficial effects of prolonged inhibition of ROCK in cardiovascular diseases have been demonstrated. The role of ROCK inhibitors in the treatment of various cardiovascular diseases was evaluated in this review.

Keywords

ROCK I, ROCK II, Rho kinase inhibitors, cardiovascular diseases

Rho Kinaz ve Kardiyovasküler Hastalıklar

Abstract

Türkçe Özet: Rho Kinase and Cardiovascular Diseases Ateroskleroz, hipertansiyon gibi arteriyel hastalıklar, düz kas hücrelerinin çoğalması ve hipertrofisi ile belirgindir. Bu hastalıkların ortak özelliği, damar düz kas hücre gerimini ve büyümesini düzenleyen endotel tabakasındaki işlev bozukluğudur. Tümör nekroze edici faktör-α, interlökin-1β gibi yangıya neden olan mediyatörler monosit kemotaktik peptit-1, damar hücre adezyon molekülü-1 ve hücrelerarası adezyon molekülü-1 gibi adezyon moleküllerinin up-regüle olarak monositlerin damar duvarında birikmesine ve adezyonuna-yapışmasına ayrıca damar düz kas hücre göçüne, çoğalmasına ve damar tıkanmasına yol açmaktadır. Küçük G proteini Rho'nun alt efektörü Rho kinaz'ın ROKα/ROCK II ve ROKβ/ROCK I olmak üzere iki izoformu bulunmaktadır. ROCK, düz kas kasılması, aktin hücre iskeleti oluşumu, hücre yapışması ve hareketliliği, çoğalması, sitokinez ve genetik bilginin genden proteine aktarılması gibi kardiyovasküler hastalıkların patojenezinde rol oynayan çeşitli hücre işlevlerine aracılık etmektedir. Fasudil ve Y-27632 gibi seçici ROCK inhibitörleri ile yapılan klinik öncesi ve klinik çalışmalarda ROCK'nin kardiyovasküler sistem ile ilgili olarak ortaya çıkan koroner vazospazm, hipertansiyon, miyokart infarktüsü, inme ve kalp yetmezliği gibi çeşitli hastalıkların patojenezinde önemli rol oynadığı gösterilmiştir. Ayrıca, ROCK'nin uzun süre baskılanmasının kardiyovasküler hastalıkların tedavisinde yararlı etkileri gösterilmiştir. Bu derlemede, ROCK inhibitörlerinin çeşitli kardiyovasküler hastalıkların tedavisindeki rolü değerlendirilmiştir.

Keywords

ROCK I, ROCK II, Rho kinaz inhibitörleri, kardiyovasküler hastalıklar

References

• I. Uelıata M. lshizaki T. Satoh H. Ono T, Kawaiıara T. Morishila T. Tamakawa l—l. Yamagami K. lnui ]. Maekawa M. Narumiya S. Calcium sensitization ol' smooth muscle mediated by a Rho—associated protein kinase in hypertension. Nature 1997; 389: 990—994.
• Dong M. Yan BP. Lian JK. Lam YY. Yip GWK and Yu CM. Rho-kinase inhibition: a novel therapeutic target for the treatment ol' cardiovascular diseases. Drug Discovery Today ;15:15—16. Shimokawu H. Rashid M.Üevclopmcnt of Rho—kinase inhibitors for cardiovascular medicine. Trends Pharmacul Sri. 2007: 28(6): 296-302.
• Mukai Y. Shimokawa H. Maloha T. Kandabashi T. Saleh S. Hiroki ]. Kaibuchi K. Takeshita A. Involvement of Rho— kinase in hypertensive vascular disease. A novel therapeutic target in hypertension. FASEBJ 2001:15:1062-1064.
• Tachibana E.. Harada T. Shibuya M. Saito K. Takayasu M. Suzuki Y. Yoshida J. [atra—arterial infusion of l‘asudil hydrochloride for treating vasnspasm following snbaraehnoid haemorı'hage. Acın Neoma-hir (Wien) ;14lzl3-—l9. Fukata Y. Amano M and Kaubuchi K. Rho—Rho—kinase pathway in smooth muscle contraction and cytoskeletai reorganization ol' non—muscle cells. Trivial-.- Prim-mum Sci 2001; 22: 32—39.
• Takai Y. Sasaki T. Matozaki T. Small GTP—binding proteins. Physio Rev 2001: S I'. l53—208.
• Hirata K. Kikuchi A. Sasaki T, Kuroda S. Involvement of rho p21 in the GTP enhanced calcium ion sensitivity of smooth ınuscle contraction. I Biol Chem 1992'. :8719—8722.
• Miura Y. Kikuehi A. Musha T, Kuroda S. Yaku H, Sasaki T, Takai Y. Regulation ol' morphology by rho p21 and its inhibitory GDPIGTP exchange protein (rho GDI) in Swiss 3T3 cells. J Bini Chem 1993'. 268:5”)—
• Shimokawa H. Takeshita A.Rho-kiaase is an important therapeutic target in cardiovascular medicine. Artermrefer Thmmb Vasc 5012005: 25(9): 1 767—751
• Chen Z. Sun _l, Pradines A. Farro G. Adnane ]. Sebti SM. Both faı'nesylated and geraııylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. . Biol Chem 2000'. :17974-8.
• Suwa H. Olıshio G. lınaınııra T. Watanabe G. Arii S. lmamura M. Narumiya S. Hiai H. Fukumolo M Overexpression ol' the rhoC gene correlates with progression ol' ductai adenocarcinoma ol' the pancreas. Br J Cancer 1998;77(1):147—52.
• Nossanıan BD, Nossaman VE, Murthy SN, Kadowitz PJRoIe ot' the RhcıMRho—kintısc pathway in the regulation of pulmonary yasoconstricıor function. Cnn J Physiol Fhm‘nmm 2010', 88(1111—8.
• Rho Kilt“: ve Kardiyolmüftüler Hosiultkltir Somlyo AP. Somlyo AV. Ca3+ sensitivity ol' smooth muscle and nonmusele myosin II: modulated by G proteins. kinases Kitazawa T. Eto M. Woodsonte TP. Khalequzzaman M. Phosphorylation of myosin phosphotase targeting subunit and Kureishi Y. Kobayasbi S. Amano M, Kimura K. Kanaide H. Nakano T. Kaibuchi K. Ito M. Rho—associated kinase directly Rolfe BE. Worth NF. World CJ. Campbell JH. Campbell Budgyn K. Marley PD. Sobey CG. Targeting rho and rho kinase in the treatment ol" ez'trtliovaseular disease. Trench Phat—mom Sci 2005: 27: 97404.
• Paeaud P. Sauzeau V. Loirand G. Rho proteins and vascular diseases. Arch Mal Coeur Vai.“ 2005'. 98: 249—254.
• Suzuki J, lzawa A. [sobe M. Antivascular cell adhesion molecule-1 and anti-very late antigen-4 monoclonal antibodies inhibit neointimal hyperplasia in the marine model of arterial injury. Atria Cordial 2004; 59: 147-152.
• Woll'ı'uın S. Detidorfer A. Rikitake Y. Stalker T.I. Gong Y, Sealia R. Dominiak P. Lian JK. Inhibition of Rlio—kinasc leads to rapid activation of phosphatidylinositol 3- kinasc/protcin kinttse Akt and cardiovascular protection. Arteriost'ler Throat ) Vase Biol 2004; 24: 18424847.
• Noma K. Oyaına N. Lino JK. Physiological role ot” ROCKs in the cardiovascular system. Am . Pitt-atio Cell Plivsioi : 290(3): (3661-8.