Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease

Nohria, Anju; Grunert, Matthew E.; Rikitake, Yoshiyuki; Noma, Kazuhiro; Pršić, Adnan; Ganz, Patricia A.; Liao, James K.; Creager, Mark A.

doi:10.1161/01.res.0000251668.39526.c7

Cited by 157 publications

(150 citation statements)

References 53 publications

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“…Several studies (20,36,37) have demonstrated a critical role for this pathway in the regulation of systemic, pulmonary, and mesenteric vascular tone. Abnormal activation of the RhoA/ROCK pathway has been implicated in the pathogenesis of hypertension by Ca 2ϩ sensitization of the contractile apparatus (28,35,43). Our results strongly implicate RhoA/ROCK as playing a pathophysiological role in PM 2.5 -mediated BP effects and cardiovascular remodeling (21,52,58).…”

Section: Discussionsupporting

confidence: 51%

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Zhao¹,

Yue²,

Xu³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

110

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Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of Ͻ2.5 m (PM2.5) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM 2.5 exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM 2.5 exposure along with increased expression of the guanine exchange factors (GEFs) PDZRhoGEF and p115 RhoGEF in PM 2.5-exposed mice. Parallel with increased RhoA activation, PM 2.5 exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM2.5 potentiates cardiac remodeling in response to ANG II through RhoA/ Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution. hypertension; vasoconstrictors; angiotensin II AMBIENT AIR POLLUTION mediated by fine particulate matter (PM) of Ͻ2.5 m in aerodynamic diameter (PM 2.5 ) has been associated with adverse cardiovascular outcomes (8,31,39,49). One important mechanism is the elevation in blood pressure (BP) that may occur within hours to days after exposure to high concentrations of PM 2.5 (6,16,21,52). Recent studies (21, 58) have shown that commonly encountered levels of airborne pollutants can result in a prohypertensive response in humans that may be exaggerated in predisposed individuals. This potentiating effect of inhaled particulates has been noted with other chronic conditions or risk factors such as atherosclerosis, diabetes, and postmenopausal status (31,40,49). Although the precise mechanisms remain elusive, there is increasing evidence that PM 2.5 exposure results in rapid changes in the vasculature (7, 32). We (51) have previously shown that PM 2.5 exposure results in the activation of RhoA/Rho-kinase (ROCK) through ROS pathways and hypothesized that this important signaling cascade may mediate at least some of the prohypertensive effects of PM 2.5 . Given the important role of RhoA/ ROCK in a multitude of processes, including the regulation of smooth muscle tone, cellular migration, and hypertrophy (36,47), in the present study we examined the effect of PM 2.5 exposure on vascular function and cardiac remodeling and tested the effects of ROCK antagonism.

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Section: Discussionsupporting

confidence: 51%

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Zhao¹,

Yue²,

Xu³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

110

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“…Other processes or conditions involving the RhoA/ ROCK pathway include angiogenesis [52], hypertension [39], cardiac hypertrophy [53], perivasclar fibrosis [54] and pulmonary hypertension [52]. Fasudil, a selective ROCK inhibitor, improves endothelial function in patients with coronary artery disease [55]. These findings suggest that ROCK inhibition might contribute to some of the pleiotropic effects of statin therapy.…”

Section: Statins and Rhomentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

Self Cite

538

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…Clinical studies have demonstrated a corelation between ROCK activity and endothelial dysfunction in patients with Coronary Artery Disease (CAD) [12]. Furthermore, treatment with the ROCK inhibitor fasudil reduced the over-activation of ROCK in patients with atherosclerosis (but not in healthy individuals) and improved endothelium-dependent vasodilation as well as flowmediated dilation (FMD), a surrogate marker for endothelial function.…”

Section: Rock and Endothelial Dysfunctionmentioning

confidence: 99%

Rock the Rock of Atherosclerosis

Xu¹

2013

J Vasc Med Surg

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A previous study from Liao's laboratory showed that macrophage ROCK1 is involved in the pathogenesis for atherosclerosis [10]. Deletion of ROCK1 in bone marrow-derived cells is atheroprotective. AbstractThe Rho-Associated Coiled-Coil Containing Protein Kinase (ROCK1 and ROCK2) were one of the downstream effectors of the small GTPase Rho. The Rho/ROCK pathway plays an important role in mediating multiple cellular processes, including endothelial dysfunction, the proliferation and migration of smooth muscle cells, foam cell formation, and arterial stiffness and aging, all of which are involved in the pathogenesis of atherosclerosis. Vascular cells (including endothelial cells, smooth muscle cells, and macrophages) undergo pathophysiological changes through the ROCK signaling pathway and ROCK inhibitors are being developed as effective therapeutic agents for atherosclerotic cardiovascular diseases. However, it is not entirely clear how ROCK isoforms are regulated, and how both isoforms contribute to the pathogenesis of atherosclerosis. A recent article from Liao's laboratory demonstrated that deletion of the ROCK2 allele in BM-derived cells attenuates plaque formation in cholesterol-fed LDLr -/-mice. Mechanistically, ROCK2 deletion decreases foam cell formation (the hallmark of atherosclerosis) by facilitating Reverse Cholesterol Transport (RCT) in macrophages, through peroxisome proliferator-activated receptor-γ/liver X receptor-α/ATP-binding cassette transporter A1 pathway. This study provides further mechanistic insight into the therapeutic benefits of ROCK2 inhibition in preventing the development of atherosclerosis.

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Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease

Cited by 157 publications

References 53 publications

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Rock the Rock of Atherosclerosis

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