This Article Full Text Full Text (PDF) All Versions of this Article: 112/19/2959    most recent CIRCULATIONAHA.105.584623v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rikitake, Y. Articles by Liao, J. K. Search for Related Content PubMed PubMed Citation Articles by Rikitake, Y. Articles by Liao, J. K. Pubmed/NCBI databases Domain Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Vascular Diseases Related Collections Remodeling Animal models of human disease Gene regulation Hypertrophy Physiological and pathological control of gene expression Genetics of cardiovascular disease

(Circulation. 2005;112:2959-2965.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Decreased Perivascular Fibrosis but Not Cardiac Hypertrophy in ROCK1^+/– Haploinsufficient Mice

Yoshiyuki Rikitake, MD, PhD^*; Naotsugu Oyama, MD, PhD^*; Chao-Yung C. Wang, MD; Kensuke Noma, MD, PhD; Minoru Satoh, MD, PhD; Hyung-Hwan Kim, PhD; James K. Liao, MD

From the Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Mass.

Correspondence to James K. Liao, MD, Brigham and Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu

Received June 14, 2005; de novo received August 22, 2005; revision received September 3, 2005; accepted September 7, 2005.

Background— Rho GTPase and its downstream target, Rho-associated kinase (ROCK), have been implicated in diverse cardiovascular diseases such as cardiac hypertrophy. However, pharmacological inhibitors of ROCK are not entirely specific, nor can they discriminate between the ROCK isoforms ROCK1 and ROCK2. To determine the specific role of ROCK1 in the development of cardiac hypertrophy, we generated ROCK1^+/– haploinsufficient mice and determined whether cardiac hypertrophy and remodeling are decreased in these mice.

Methods and Results— Litters of ROCK1^–/– mice on C57Bl/6 background were markedly underrepresented, suggesting lethality in utero or postnatally. ROCK1^+/– mice, however, are viable and fertile with no obvious phenotypic abnormalities. Basal blood pressure, heart rate, and cardiac dimension and function in ROCK1^+/– mice were similar to those in wild-type (WT) littermates. Infusion of angiotensin II (400 ng · kg^–1 · min^–1 for 28 days) or treatment with N^G-nitro-L-arginine methyl ester (1 mg/mL in drinking water for 28 days) caused similar increases in systolic blood pressure, left ventricular wall thickness, left ventricular mass, ratio of heart weight to tibial length, and cardiomyocyte size in ROCK1^+/– mice and WT littermates. In contrast, perivascular fibrosis in hearts was increased to a lesser extent in ROCK1^+/– mice compared with WT littermates. This was associated with decreased expression of transforming growth factor-ß, connective tissue growth factor, and type III collagen. In addition, perivascular fibrosis induced by transaortic constriction or myocardial infarction was decreased in ROCK1^+/– mice compared with WT littermates.

Conclusions— These findings indicate ROCK1 is critical for the development of cardiac fibrosis, but not hypertrophy, in response to various pathological conditions and suggest that signaling pathways leading to the hypertrophic and profibrotic response of the heart are distinct.

Key Words: blood pressure • hypertension • hypertrophy • remodeling • angiotensin

This article has been cited by other articles:

				N. Sawada, H. Itoh, K. Miyashita, H. Tsujimoto, M. Sone, K. Yamahara, Z. P. Arany, F. Hofmann, and K. Nakao Cyclic GMP Kinase and RhoA Ser188 Phosphorylation Integrate Pro- and Antifibrotic Signals in Blood Vessels Mol. Cell. Biol., November 15, 2009; 29(22): 6018 - 6032. [Abstract] [Full Text] [PDF]

				J Lartey and A Lopez Bernal RHO protein regulation of contraction in the human uterus Reproduction, September 1, 2009; 138(3): 407 - 424. [Abstract] [Full Text] [PDF]

				S. B. Haudek, D. Gupta, O. Dewald, R. J. Schwartz, L. Wei, J. Trial, and M. L. Entman Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation Cardiovasc Res, August 1, 2009; 83(3): 511 - 518. [Abstract] [Full Text] [PDF]

				A. Jadhav and J. F. Ndisang Heme Arginate Suppresses Cardiac Lesions and Hypertrophy in Deoxycorticosterone Acetate-Salt Hypertension Experimental Biology and Medicine, July 1, 2009; 234(7): 764 - 778. [Abstract] [Full Text] [PDF]

				Z. Ying, P. Yue, X. Xu, M. Zhong, Q. Sun, M. Mikolaj, A. Wang, R. D. Brook, L. C. Chen, and S. Rajagopalan Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1540 - H1550. [Abstract] [Full Text] [PDF]

				N. Gellings Lowe, J. S. Swaney, K. M. Moreno, and R. A. Sabbadini Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-{beta}-stimulated collagen production by cardiac fibroblasts Cardiovasc Res, May 1, 2009; 82(2): 303 - 312. [Abstract] [Full Text] [PDF]

				S. Hsu, T. Nagayama, N. Koitabashi, M. Zhang, L. Zhou, D. Bedja, K. L. Gabrielson, J. D. Molkentin, D. A. Kass, and E. Takimoto Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway Cardiovasc Res, February 1, 2009; 81(2): 301 - 309. [Abstract] [Full Text] [PDF]

				D. P. Del Re, S. Miyamoto, and J. H. Brown Focal Adhesion Kinase as a RhoA-activable Signaling Scaffold Mediating Akt Activation and Cardiomyocyte Protection J. Biol. Chem., December 19, 2008; 283(51): 35622 - 35629. [Abstract] [Full Text] [PDF]

				P. P. Ongusaha, H. H. Qi, L. Raj, Y.-B. Kim, S. A. Aaronson, R. J. Davis, Y. Shi, J. K. Liao, and S. W. Lee Identification of ROCK1 as an Upstream Activator of the JIP-3 to JNK Signaling Axis in Response to UVB Damage Sci. Signal., November 25, 2008; 1(47): ra14 - ra14. [Abstract] [Full Text] [PDF]

				A. Jadhav, E. Torlakovic, and J. F. Ndisang Interaction Among Heme Oxygenase, Nuclear Factor-{kappa}B, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension Hypertension, November 1, 2008; 52(5): 910 - 917. [Abstract] [Full Text] [PDF]

				H.-W. Wang, P.-Y. Liu, N. Oyama, Y. Rikitake, S. Kitamoto, J. Gitlin, J. K. Liao, and W. A. Boisvert Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice FASEB J, October 1, 2008; 22(10): 3561 - 3570. [Abstract] [Full Text] [PDF]

				H. Ohtsu, S. Higuchi, H. Shirai, K. Eguchi, H. Suzuki, A. Hinoki, E. Brailoiu, A. D. Eckhart, G. D. Frank, and S. Eguchi Central Role of Gq in the Hypertrophic Signal Transduction of Angiotensin II in Vascular Smooth Muscle Cells Endocrinology, July 1, 2008; 149(7): 3569 - 3575. [Abstract] [Full Text] [PDF]

				A. Phrommintikul, L. Tran, A. Kompa, B. Wang, A. Adrahtas, D. Cantwell, D. J. Kelly, and H. Krum Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1804 - H1814. [Abstract] [Full Text] [PDF]

				S. L.M. Peters and M. C. Michel The RhoA/Rho kinase pathway in the myocardium Cardiovasc Res, July 1, 2007; 75(1): 3 - 4. [Full Text] [PDF]

				M. Satoh, C. M. Matter, H. Ogita, K. Takeshita, C.-Y. Wang, G. W. Dorn II, and J. K. Liao Inhibition of Apoptosis-Regulated Signaling Kinase-1 and Prevention of Congestive Heart Failure by Estrogen Circulation, June 26, 2007; 115(25): 3197 - 3204. [Abstract] [Full Text] [PDF]

				P.-Y. Liu, J.-H. Chen, L.-J. Lin, and J. K. Liao Increased Rho Kinase Activity in a Taiwanese Population With Metabolic Syndrome J. Am. Coll. Cardiol., April 17, 2007; 49(15): 1619 - 1624. [Abstract] [Full Text] [PDF]

				H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells Hypertension, October 1, 2006; 48(4): 534 - 540. [Full Text] [PDF]

				J. Chang, M. Xie, V. R. Shah, M. D. Schneider, M. L. Entman, L. Wei, and R. J. Schwartz Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis PNAS, September 26, 2006; 103(39): 14495 - 14500. [Abstract] [Full Text] [PDF]

				S. Chrissobolis and C. G. Sobey Recent Evidence for an Involvement of Rho-Kinase in Cerebral Vascular Disease Stroke, August 1, 2006; 37(8): 2174 - 2180. [Abstract] [Full Text] [PDF]

				M. Satoh, H. Ogita, K. Takeshita, Y. Mukai, D. J. Kwiatkowski, and J. K. Liao Requirement of Rac1 in the development of cardiac hypertrophy PNAS, May 9, 2006; 103(19): 7432 - 7437. [Abstract] [Full Text] [PDF]

				Y.-M. Zhang, J. Bo, G. E. Taffet, J. Chang, J. Shi, A. K. Reddy, L. H. Michael, M. D. Schneider, M. L. Entman, R. J. Schwartz, et al. Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis FASEB J, May 1, 2006; 20(7): 916 - 925. [Abstract] [Full Text] [PDF]

				J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]

				K. Noma, N. Oyama, and J. K. Liao Physiological role of ROCKs in the cardiovascular system Am J Physiol Cell Physiol, March 1, 2006; 290(3): C661 - C668. [Abstract] [Full Text] [PDF]