Importance of Rac1 Signaling Pathway Inhibition in the Pleiotropic Effects of HMG-CoA Reductase Inhibitors

Rashid, Mamunur; Tawara, Shunsuke; Fukumoto, Yoshihiro; Seto, Minoru; Yano, Kazuo; Shimokawa, Hiroaki

doi:10.1253/circj.cj-08-0817

Cited by 78 publications

(79 citation statements)

References 32 publications

(25 reference statements)

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“…This is consistent with a number of studies showing the mitochondria to be the main site of action of the noncholesterol effects of statins (3). Multiple studies have shown that statin treatment impacts on the prenylation of small GTPases (35)(36)(37), and the present study establishes a clear link between prenylation inhibition and impaired mitochondria homeostasis. It seems likely that inhibition of protein prenylation should impact many cellular processes and organelles besides the mitochondria.…”

Section: Discussionsupporting

confidence: 75%

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Rauthan

Ranji

Pradenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

137

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Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.

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Section: Discussionsupporting

confidence: 75%

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Rauthan

Ranji

Pradenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

137

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“…9 Furthermore, it was also been demonstrated that the pleiotropic effects of statins are mediated predominantly though inhibition of the Rac1 signaling pathway, but not the RhoA/Rho-kinase or Ras signaling pathway, at the clinical and maximum doses used in Asian countries. 10 In their study, Rashid et al found that the clinical concentration/dose of statins only inhibited Rac1 in vitro and in vivo, suggesting that combination therapy with statins and Rho-kinase inhibitors would be effective for cardiovascular diseases. 10 My group also demonstrated that intraarterial infusion of a Rho-kinase inhibitor, fasudil, causes a preferential increase in forearm blood flow in patients with heart failure, compared with control subjects.…”

Section: Article P 1409mentioning

confidence: 99%

“…10 In their study, Rashid et al found that the clinical concentration/dose of statins only inhibited Rac1 in vitro and in vivo, suggesting that combination therapy with statins and Rho-kinase inhibitors would be effective for cardiovascular diseases. 10 My group also demonstrated that intraarterial infusion of a Rho-kinase inhibitor, fasudil, causes a preferential increase in forearm blood flow in patients with heart failure, compared with control subjects. 11 Taking together the benefits of statins on the mevaonate pathway and the results of Han et al, statins should be administered to the patients with hypertension.…”

Section: Article P 1409mentioning

confidence: 99%

Mevalonate Pathway Is a Novel Target for Hypertension

Kishi

2011

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp he mevalonate pathway is an important metabolic pathway that plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, like cholesterol, and non-sterol isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). 1 These non-sterol isoprenoid intermediates of the mevalonate biosynthetic pathway play important roles in the post-translational modification of small GTP-binding proteins (GTPases), such as Ras and Rho. FPP and GGPP are important lipid attachments for the post-translational modification of a variety of cellular proteins, including the Ras and Rho family small G proteins. 2,3 Isoprenylation of small G proteins is critical for their regulation of intracellular trafficking and the interactions with their regulators and effectors. 2,3 For instance, modification with FPP is necessary for proper localization of Ras family small G proteins, whereas GGPP is required for that of Rho family small G proteins. 2,3 It has been demonstrated that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) prevent isoprenylation of Rho family small G proteins, which inhibits these signaling molecules. 4-7 Article p 1409In this issue of the Journal, Han et al examined the expression of key enzymes in the mevalonate pathway in liver, heart and aorta during the process of hypertension in spontaneously hypertensive rats (SHR), including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), phospho-HMGR, farnesyl diphosphate synthase, squalene synthase, farnesyltransferase (FNT) α, FNT β and geranylgeranyltransferase type I (GGTase-I). 8 The study results suggest that alteration of key enzyme expressions in the mevalonate pathway in the heart and aorta are implicated in the process of cardiovascular remodeling in SHR, probably through activating small GTPases. 8 Because cardiovascular remodeling in hypertension causes and indicates various organ damage, these results also suggest that the mevalonate pathway should be inhibited in hypertension.Statins have beneficial effects on cardiovascular and cerebrovascular diseases, including acute coronary syndrome and stroke. Many previous studies have suggest that pleiotropic effects of statins are thought to be mediated through inhibition of small GTP-binding proteins, such as Rho, Rac and Ras, whose correct membrane localization and GTPase activity are dependent on isoprenylation. 4-7 Statins could also inhibit the synthesis of important isoprenoid intermediates, such as FPP and GGPP, which lie downstream from l-mevalonic acid. 1 These intermediates serve as important lipid attachments for the post-translational modification of intracellular proteins such as nuclear lamins, Ras, Rho, Rac and Rap. 7 Among them, Rho-kinase is one of the downstream effectors of the small G-protein, Rho. Previous reports show that both the Rho/Rho-kinase and Rac pathway may be involved in the pathogenesis of cardiovascula...

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“…As a parameter of aortic atherosclerosis, the percentage of the plaque area stained by Oil Red O to the total luminal surface area was determined (Nakano et al 2010). Histological studies were performed for determination of cardiomyocyte cross-sectional area, medial thickness (the ratio of medial thickness to internal diameter), perivascular fibrosis (the ratio of the fibrosis area surrounding the vessel to the total vessel area) and fibrosis area of the kidneys and liver (the ratio of fibrosis area to cross-sectional area), as previously reported (Lumeng et al 2007;Rashid et al 2009;Gandhi et al 2012). The heart, kidneys and liver were fixed for 24-30 hours at room temperature in 4% PFA (paraformaldehyde) (Sigma Chemical Co) and embedded in paraffin.…”

Section: Histological and Immunohistochemical Analysismentioning

confidence: 99%

“…2C). We next evaluated cardiomyocyte hypertrophy as it is linked to cardiac hypertrophy (Rashid et al 2009). The extent of cardiomyocyte cross-sectional area was also increased in Untreated and was significantly suppressed only in OLM+AZL, whereas systolic blood pressure was unaltered (Fig.…”

Section: Effects Of the Drug Treatments On The Coronary Artery And Camentioning

confidence: 99%

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Noda

Hosoya

Nakajima

et al. 2012

Tohoku J. Exp. Med.

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Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE −/− ) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE −/− mice. Diabetic ApoE −/− mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE −/− mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.

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Importance of Rac1 Signaling Pathway Inhibition in the Pleiotropic Effects of HMG-CoA Reductase Inhibitors

Cited by 78 publications

References 32 publications

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Mevalonate Pathway Is a Novel Target for Hypertension

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

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