James K Liao

University of Chicago, Chicago, Illinois, United States

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Publications (190)1417.32 Total impact

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    ABSTRACT: The RhoA/Rho-associated kinase (ROCK) pathway has a key physiological role in the pathogenesis of atherosclerosis. Increased ROCK activity is associated with cardiovascular diseases. Endogenous nitric oxide (NO) has an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in patients with angina pectoris. This is a prospective, open-label, randomized, controlled study. A total of 30 patients with angina pectoris were randomly assigned to receive 40 mg day(-1) of isosorbide mononitrate (n=15, 12 men and 3 women, mean age of 63±12 years, isosorbide mononitrate group) or conventional treatment (n=15, 13 men and 2 women, mean age of 64±13 years, control group) for 12 weeks. ROCK activity in peripheral leukocytes was measured by western blot analysis. ROCK activities at 4 and 12 weeks after treatment were decreased in the isosorbide mononitrate group (0.82±0.33 at 0 week, 0.62±0.20 at 4 weeks, 0.61±0.19 at 12 weeks, n=15 in each group, P<0.05, respectively) but not altered in the control group. ROCK1 and ROCK2 expression levels were similar in all treatment periods in the two groups. These findings suggest that the administration of exogenous NO can inhibit ROCK activity, indicating that the usage of exogenous NO could have a protective effect in patients with angina pectoris.Hypertension Research advance online publication, 5 March 2015; doi:10.1038/hr.2015.24.
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    ABSTRACT: The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases (ROCKs) in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma (APA), 23 patients with idiopathic hyperaldosteronism (IHA), and 40 age-, sex-, and blood pressure-matched patients with essential hypertension (EHT). FMD was significantly lower in the APA group than in the IHA and EHT groups (3.2±2.0% versus 4.6±2.3% and 4.4±2.2%; P<0.05, respectively), whereas there was no significant difference in FMD between the IHA and EHT groups. There was no significant difference in nitroglycerine-induced vasodilation in the 3 groups. ROCK activity was higher in the APA group than in the IHA and EHT groups (1.29±0.57 versus 1.00±0.46 and 0.81±0.36l; P<0.05, respectively), whereas there was no significant difference in ROCK activity between the IHA and EHT groups. FMD correlated with age (r=-0.31; P<0.01), plasma aldosterone concentration (r=-0.35; P<0.01), and aldosterone:renin ratio (r=-0.34; P<0.01). ROCK activity correlated with age (r=-0.24; P=0.04), plasma aldosterone concentration (r=0.33; P<0.01), and aldosterone:renin ratio (r=0.46; P<0.01). After adrenalectomy, FMD and ROCK activity were restored in patients with APA. APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EHT. APA may have a higher risk of future cardiovascular events. © 2015 American Heart Association, Inc.
    Hypertension 01/2015; 65(4). DOI:10.1161/HYPERTENSIONAHA.114.05001 · 7.63 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. IPF is thought to result from repetitive environmental injury to the lung epithelium, in the context of aberrant host wound healing responses. Tissue responses to injury fundamentally involve reorganization of the actin cytoskeleton of participating cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages. Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine/threonine kinases (ROCK1 and ROCK2). As would therefore be expected, lung ROCK activation has been demonstrated in humans with IPF and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis. Here we review ROCK structure and function, upstream activators and downstream targets of ROCKs in pulmonary fibrosis, contributions of ROCKs to profibrotic cellular responses to lung injury, ROCK inhibitors and their efficacy in animal models of pulmonary fibrosis, and potential toxicities of ROCK inhibitors in humans, as well as involvement of ROCKs in fibrosis in other organs. As we discuss, ROCK activation is required for multiple profibrotic responses, in the lung and multiple other organs, suggesting ROCK participation in fundamental pathways that contribute to the pathogenesis of a broad array of fibrotic diseases. Multiple lines of evidence therefore indicate that ROCK inhibition has great potential to be a powerful therapeutic tool in the treatment of fibrosis, both in the lung and beyond.
    Pharmacological reviews 01/2015; 67(1):103-117. DOI:10.1124/pr.114.009381 · 18.55 Impact Factor
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    ABSTRACT: Derangement of Rho-associated kinases (ROCKs) has been related to coronary artery disease and stroke. ROCK2, rather than ROCK1, plays a predominant role in vascular contractility. The present study aims to test (1) the associations between ROCK2 single nucleotide polymorphisms (SNPs) and arterial stiffness, and (2) the molecular mechanism accounting for their effects. Stiffness parameters including beta (β), elasticity modulus (Ep) and pulse wave velocity (PWV) were obtained by carotid ultrasonography. Seven tagging SNPs of ROCK2 were initially genotyped in 856 subjects and significant SNPs were replicated in another group of 527 subjects. Two SNPs in complete linkage disequilibrium were found to be significantly associated with arterial stiffness. The major alleles of rs978906 (A allele) and rs9808232 (C allele) were associated with stiffer arteries. SNP rs978906 was predicted to influence microRNA(miR)-1183s binding to ROCK2, while rs9808232 causes amino acid substitution. To determine their functional impact, plasmid constructs carrying different alleles of the significant SNPs were created. Compared to rs978906G-allele constructs, cells transfected with rs978906A-allele constructs had higher baseline luciferase activities and were less responsive to miR-1183 changes. Oxidized-low density lipoprotein (Ox-LDL) suppressed miR-1183 levels and increased ROCK2 protein amounts. For rs9808232, cells transfected with C-allele constructs had significantly higher ROCK activities than those with A-allele constructs. Leukocyte ROCK activities were further measured in 52 healthy subjects. The average ROCK activity was highest in human subjects with CC genotype at rs9808232, followed by those with AC and lowest in AA. Taken together, the present study showed that two functional SNPs of ROCK2 increase susceptibility of arterial stiffness in the Chinese population. Non-synonymous SNP rs9808232 influences ROCK2 activity, while 3' UTR SNP rs978906 affects the ROCK2 protein synthesis by interfering miR-1183s binding. Copyright © 2013. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 12/2014; 79. DOI:10.1016/j.yjmcc.2014.11.023 · 5.15 Impact Factor
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    ABSTRACT: Rho-associated kinase (ROCK) signaling pathway has been shown to mediate various cellular functions including cell proliferation, migration, adhesion, apoptosis, and contraction, all of which may be involved in pathogenesis of atherosclerosis. Endogenous nitric oxide (NO) is well known to have an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in vascular smooth muscle cells (VSMCs) in vitro and in vivo.
    PLoS ONE 10/2014; 9(10):e109017. DOI:10.1371/journal.pone.0109017 · 3.53 Impact Factor
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    ABSTRACT: Background Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leukocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast-cell dependent model of allergic airways disease.Methods and ResultsRepeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wildtype (WT) mice. OVA- induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2+/-) or ROCK1 (ROCK1+/-), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1+/- versus WT mice. However, in ROCK2+/- mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1+/- and ROCK2+/- versus WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses.Conclusion In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast-cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia.This article is protected by copyright. All rights reserved.
    Clinical & Experimental Allergy 10/2014; DOI:10.1111/cea.12438 · 4.32 Impact Factor
  • International Journal of Cardiology 07/2014; 176(1). DOI:10.1016/j.ijcard.2014.06.059 · 6.18 Impact Factor
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  • Yanying Miao, James K Liao
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    ABSTRACT: Stroke is a leading cause of death and serious long-term disability. Ischemic stroke is the major subtype of stroke. Currently, its diagnosis is mainly dependent upon clinical symptoms and neuroimaging techniques. Despite these clinical and imaging modalities, often strokes are not recognized after initial onset. As early intervention of medical or surgical therapy is often associated with improved outcomes, there is an urgent need to improve the speed and accuracy of stroke diagnosis. Stroke is a complex pathophysiological process involving; energy failure, imbalance of ion homeostasis, acidosis, intracellular calcium overload, neuronal excitotoxicity, free radical-mediated lipid oxidation, inflammatory cell infiltration, and glial cell activation. These events ultimately lead to neuronal apoptotic cell death or necrosis. In this review, we have summarized the serum biomarkers according to the pathophysiological processes of stroke, which have been intensively studied in clinical trials of stroke over the past five years, and also used Medline's 'related article' option to identify further articles. We focused on the potential biomarkers pertaining to vascular injury, metabolic changes, oxidative injury, and inflammation, and newly studied biomarkers, and discussed how these biomarkers could be used for the diagnosis or determining the prognosis of stroke.
    Expert Review of Neurotherapeutics 01/2014; DOI:10.1586/14737175.2014.875471 · 2.96 Impact Factor
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    ABSTRACT: Cardiovascular diseases are associated with chronic activation of Rho-associated kinase. Rho-associated kinase activity is significantly correlated with endothelial function and Framingham risk score. However, there is no information on the prognostic value of Rho-associated kinase activity. We evaluated Rho-associated kinase activity in peripheral leukocytes by Western blot analysis in 633 subjects who underwent health-screening examination at Hiroshima University Hospital. We assessed the associations between Rho-associated kinase activity and first major cardiovascular events (death from cardiovascular causes, myocardial infarction, and stroke), death from cardiovascular causes, acute myocardial infarction, stroke, revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and hospitalization for heart failure. During a median period of 42.0 months (interquartile range, 24.4-56.6 months) of follow-up, 29 subjects died (10 from cardiovascular causes), 2 myocardial infarction, 20 revascularization, 15 stroke, and 17 hospitalization for heart failure. After adjustment for age, sex, cardiovascular risk factors, and other relevant variables, Rho-associated kinase activity remained a strong independent indicator of first major cardiovascular events (hazard ratio, 2.19; 95% confidence interval, 1.35-3.70; P=0.002), death from cardiovascular disease (hazard ratio, 2.57; 95% confidence interval, 1.18-6.60; P=0.002), stroke (hazard ratio, 2.14; 95% confidence interval, 1.24-3.86; P=0.006), and revascularization (hazard ratio, 2.68; 95% confidence interval, 1.60-4.66; P<0.001). Leukocyte Rho-associated kinase activity may be a new biomarker of cardiovascular events. These findings suggest that inhibition of Rho-associated kinase activity may be a therapeutic target for prevention of cardiovascular events.
    Hypertension 12/2013; 63(4). DOI:10.1161/HYPERTENSIONAHA.113.02296 · 7.63 Impact Factor
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    ABSTRACT: Recent animal and human studies have demonstrated the importance of RhoA/Rho-associated kinases (ROCKs) pathway in ischemic stroke (IsST). Whether the genetic variation within ROCKs-associated genes modulates IsST risk remains elusive. The association between 66 tag-SNPs (tSNPs) of 3 ROCKs-associated genes (ROCK1, ROCK2 and ARHGEF10) and incident IsST was investigated in 23,294 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cancer and cardiovascular disease at baseline. During a 15-year follow-up period, 323 participants developed a first ever IsST. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and IsST risk assuming an additive genetic model. Haplotype-block analysis was also performed. A total of ten tSNPs were associated with IsST risk (three in ARHGEF10, and seven in ROCK1; all p<0.050). Further investigation using the haplotype-block analysis revealed similar significant association of pre-specified haplotypes of ROCK1 with IsST risk (p=0.005). If corroborated in other large prospective studies, the present findings suggest that genetic variation within the ROCKs-associated pathway gene loci examined, in particular, the ROCK1 gene variation may influence IsST risk.
    Clinical Science 12/2013; DOI:10.1042/CS20130652 · 5.63 Impact Factor
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  • Naoki Sawada, James K Liao
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    ABSTRACT: Significance: The HMG-CoA reductase inhibitors or statins are important therapeutic agents for lowering serum cholesterol levels. However, recent studies suggest that statins may exert atheroprotective effects beyond cholesterol lowering. These so-called "pleiotropic effects" include effects of statins on vascular and inflammatory cells. Thus, it is important to understand whether other signaling pathways that are involved in atherosclerosis could be targets of statins, and if so, whether individuals with "over-activity" of these pathways could benefit from statin therapy, regardless of serum cholesterol level. Recent Advances: Statins inhibit the synthesis of isoprenoids, which are important for the function of the Rho/Rho-associated coiled-coil containing kinase (ROCK) pathway. Indeed, recent studies suggest that inhibition of the Rho/ROCK pathway by statins could lead to improved endothelial function and decreased vascular inflammation and atherosclerosis. Thus, the Rho/ROCK pathway has emerged as an important target of statin therapy for reducing atherosclerosis and possibly cardiovascular disease. Critical Issues: Because atherosclerosis is both a lipid and an inflammatory disease, it is important to understand how inhibition of Rho/ROCK pathway could contribute to statins' anti-atherosclerotic effects. Future Directions: The role of ROCKs (ROCK1 and ROCK2) in endothelial, smooth muscle, and inflammatory cells needs to be determined in the context of atherogenesis. This could lead to the development of specific ROCK1 or ROCK2 inhibitors, which could have greater therapeutic benefits with less toxicity. Also, clinical trials will need to be performed to determine whether inhibition of ROCKs, with and without statins, could lead to further reduction in atherosclerosis and cardiovascular disease.
    Antioxidants & Redox Signaling 08/2013; DOI:10.1089/ars.2013.5524 · 8.20 Impact Factor
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    Ming Dong, Xin Jiang, James K Liao, Bryan P Yan
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    ABSTRACT: BACKGROUND: Recent evidence suggests that Rho-kinase (ROCK) plays an important role in the pathogenesis of atherosclerosis and a marker of atherosclerotic burden. Polyvascular disease with concomitant peripheral arterial disease (PAD) and coronary artery disease (CAD) is common and associated with a worse prognosis. The aim of this study was to evaluate ROCK activity as a marker of polyvascular disease. HYPOTHESIS: METHODS: We retrospectively analyzed patients undergoing coronary angiography at our institution between February 2009 and May 2009. Patients with only CAD (n = 40) defined by coronary artery stenosis of ≥50% by angiography, only PAD (n = 40) defined by an ankle brachial index (ABI) <0.9, and combined CAD/PAD (n = 40) were matched by age and sex to control patients (n = 40) without CAD or PAD. ROCK activity was determined by phosphorylation of the myosin binding subunit in leukocytes and then compared between each group. Multivariate analysis was used to determine independent predictors of polyvascular disease. Discriminative ability of elevated ROCK activity was assessed using receiver operator characteristics (ROC) curves. RESULTS: Patients (age 68 ± 12 years, 79% male) with CAD, PAD, and CAD/PAD had a mean ABI of 1.08, 0.62, and 0.65, respectively, compared to 1.08 in the control group. There was an incremental increase in ROCK activity in patients with CAD (4.61 ± 2.11), PAD (4.27 ± 1.39), and CAD/PAD (5.96 ± 1.94) compared to control (2.40 ± 0.43) (all P < 0.05). ROCK activity (odds ratio: 4.53, 95% confidence interval: 1.26-6.30) was an independent predictor of polyvascular disease. The ROCK cutoff value of 4.85 had a sensitivity of 72.7% and a specificity of 65.7%, with an area under ROC curve of 0.71 for polyvascular disease. CONCLUSIONS: Patients with concomitant peripheral and coronary arterial disease are associated with increased Rho-kinase activity. Rho-kinase activity may be a potential marker of atherosclerotic burden for patients with polyvascular disease.
    Clinical Cardiology 06/2013; 36(6). DOI:10.1002/clc.22118 · 2.23 Impact Factor
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    ABSTRACT: OBJECTIVE: The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells. APPROACH AND RESULTS: In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II-induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II-induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol. CONCLUSIONS: These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2013; 33(7). DOI:10.1161/ATVBAHA.112.300922 · 6.34 Impact Factor
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    ABSTRACT: INTRODUCTION.: Activated RhoA/Rho kinase (ROCK) has been implicated in diabetes-induced erectile dysfunction. Earlier studies have demonstrated involvement of ROCK pathway in the activation of arginase in endothelial cells. However, signaling pathways activated by ROCK in the penis remain unclear. AIM.: We tested whether ROCK and p38 MAPK are involved in the elevation of arginase activity and subsequent impairment of corpora cavernosal (CC) relaxation in diabetes. METHODS.: Eight weeks after streptozotocin-induced diabetes, vascular functional studies, arginase activity assay, and protein expression of RhoA, ROCK, phospho-p38 MAPK, p38 MAPK, phospho-MYPT-1(Thr850) , MYPT-1 and arginase levels were assessed in CC tissues from nondiabetic wild type (WT), diabetic (D) WT (WT + D), partial ROCK 2(+/-) knockout (KO), and ROCK 2(+/-) KO + D mice. MAIN OUTCOME MEASURES.: The expression of RhoA, ROCK 1 and 2, phosphorylation of MYPT-1(Thr850) and p38 MAPK, arginase activity/expression, endothelial- and nitrergic-dependent relaxation of CC was assayed. RESULTS.: Diabetes significantly reduced maximum relaxation (Emax ) to both endothelium-dependent acetylcholine (WT + D: Emax ; 61 ± 4% vs. WT: Emax ; 75 ± 2%) and nitrergic nerve stimulation. These effects were associated with increased expression of active RhoA, ROCK 2, phospho-MYPT-1(Thr850) , phospho-p38 MAPK, arginase II, and activity of corporal arginase (1.6-fold) in WT diabetic CC. However, this impairment in CC of WT + D mice was absent in heterozygous ROCK 2(+/-) KO + D mice for acetylcholine (Emax : 80 ± 5%) and attenuated for nitrergic nerve-induced relaxation. CC of ROCK 2(+/-) KO + D mice showed much less ROCK activity, did not exhibit p38 MAPK activation, and had reduced arginase activity and arginase II expression. These findings indicate that ROCK 2 mediates diabetes-induced elevation of arginase activity. Additionally, pretreatment of WT diabetic CC with inhibitors of arginase (ABH) or p38 MAPK (SB203580) partially prevented impairment of ACh- and nitrergic nerve-induced relaxation and elevation of arginase activity. CONCLUSION.: ROCK 2, p38 MAPK and arginase play key roles in diabetes-induced impairment of CC relaxation.
    Journal of Sexual Medicine 04/2013; DOI:10.1111/jsm.12134 · 3.15 Impact Factor
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    ABSTRACT: The Rho-associated coiled-coil containing kinases, ROCK1 and ROCK2, are important regulators of cell shape, migration, and proliferation through effects on the actin cytoskeleton. However, it is not known whether ROCK2 plays an important role in the development of cardiac hypertrophy. To determine whether the loss of ROCK2 could prevent cardiac hypertrophy, cardiomyocyte-specific ROCK2-null (c-ROCK2(-/-)) were generated using conditional ROCK2(flox/flox) mice and α-myosin heavy-chain promoter-driven Cre recombinase transgenic mice. Cardiac hypertrophy was induced by Ang II infusion (400 ng/kg/min, 28 d) or transverse aortic constriction (TAC). Under basal conditions, hemodynamic parameters, cardiac anatomy, and function of c-ROCK2(-/-) mice were comparable to wild-type (WT) mice. However, following Ang II infusion or TAC, c-ROCK2(-/-) mice exhibited a substantially smaller increase in heart-to-body weight ratio, left ventricular mass, myocyte cross-sectional area, hypertrophy-related fetal gene expression, intraventricular fibrosis, cardiac apoptosis, and oxidative stress compared to control mice. Deletion of ROCK2 in cardiomyocytes leads to increased expression of four-and-a-half LIM-only protein-2 (FHL2) and FHL2-mediated inhibition of serum response factor (SRF) and extracellular signal-regulated mitogen-activated protein kinase (ERK). Knockdown of FHL2 expression in ROCK2-deficient cardiomyocytes or placing ROCK2-haploinsufficient (ROCK2(+/-)) mice on FHL2(+/-)-haploinsufficient background restored the hypertrophic response to Ang II. These results indicate that cardiomyocyte ROCK2 is essential for the development of cardiac hypertrophy and that up-regulation of FHL2 may contribute to the antihypertrophic phenotype that is observed in cardiac-specific ROCK2-deficient mice.-Okamoto, R., Li, Y., Noma, K., Hiroi, Y., Liu, P.-Y., Taniguchi, M., Ito, M., Liao, J. K. FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2.
    The FASEB Journal 12/2012; 27(4). DOI:10.1096/fj.12-217018 · 5.48 Impact Factor

Publication Stats

12k Citations
1,417.32 Total Impact Points


  • 2014–2015
    • University of Chicago
      • Section of Cardiology
      Chicago, Illinois, United States
  • 2013–2015
    • The University of Chicago Medical Center
      • Section of Cardiology
      Chicago, Illinois, United States
    • Tokyo Medical and Dental University
      • Department of Molecular Endocrinology and Metabolism
      Edo, Tōkyō, Japan
  • 2012
    • Spaulding Rehabilitation Hospital
      • Department of Physical Medicine and Rehabilitation
      Boston, MA, United States
    • Chang Gung Memorial Hospital
      • Division of Cardiology
      T’ai-pei, Taipei, Taiwan
  • 2010–2012
    • The Chinese University of Hong Kong
      • Department of Medicine and Therapeutics
      Hong Kong, Hong Kong
  • 1999–2012
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1998–2011
    • Brigham and Women's Hospital
      • • Vascular Medicine Research Group
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2000–2009
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Johannes Gutenberg-Universität Mainz
      • III. Department of Medicine
      Mainz, Rhineland-Palatinate, Germany
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 2008
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2007
    • National Cheng Kung University
      • Department of Internal Medicine
      臺南市, Taiwan, Taiwan
  • 2006
    • Imperial College London
      • Faculty of Medicine
      Londinium, England, United Kingdom
  • 2005
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2004
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 2003
    • University of Texas Southwestern Medical Center
      • Department of Biochemistry
      Dallas, TX, United States
    • Medical University of South Carolina
      • Department of Biochemistry and Molecular Biology (College of Medicine)
      Charleston, South Carolina, United States
  • 2002
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 1997
    • University of Massachusetts Boston
      Boston, Massachusetts, United States